Anti-obesity 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles

ABSTRACT

The present invention is directed to 1,2,3,4,10,10a-hexahydropyrazino [1,2-a]indole derivatives of formula (I): 
                 
 
as well as pharmaceutically acceptable salts, hydrates and esters thereof, wherein the substituents have the meanings provided in the specification. Compounds of the present invention may be used in the treatment or prevention of obesity or Type II diabetes.

CONTINUITY INFORMATION

This application is a continuation of Ser. No. 09/912,949, filed Jul.25, 2001 now abandoned.

BACKGROUND OF THE INVENTION

It has been recognised that obesity is a disease process influenced byenvironmental factors in which the traditional weight loss methods ofdieting and exercise need to be supplemented by therapeutic products (S.Parker, “Obesity: Trends and Treatments”, Scrip Reports, PJBPublications Ltd, 1996).

Whether someone is classified as overweight or obese is generallydetermined on the basis of their body mass index (BMI) which iscalculated by dividing body weight (kg) by height squared (m²). Thus,the units of BMI are kg/m² and it is possible to calculate the BMI rangeassociated with minimum mortality in each decade of life. Overweight isdefined as a BMI in the range 25-30 kg/m², and obesity as a BMI greaterthan 30 kg/m². There are problems with this definition in that it doesnot take into account the proportion of body mass that is muscle inrelation to fat (adipose tissue). To account for this, obesity can alsobe defined on the basis of body fat content: greater than 25% and 30% inmales and females, respectively.

As the BMI increases there is an increased risk of death from a varietyof causes that is independent of other risk factors. The most commondiseases with obesity are cardiovascular disease (particularlyhypertension), diabetes, including Type I and Type II diabetes, (obesityaggravates the development of diabetes), gall bladder disease(particularly cancer) and diseases of reproduction. Research has shownthat even a modest reduction in body weight can correspond to asignificant reduction in the risk of developing coronary heart disease.

Compounds marketed as anti-obesity agents include Orlistat (XENICAL®)and Sibutramine. Orlistat (a lipase inhibitor) inhibits fat absorptiondirectly and tends to produce a high incidence of unpleasant (thoughrelatively harmless) side-effects such as diarrhoea. Sibutramine (amixed 5-HT/noradrenaline reuptake inhibitor) can increase blood pressureand heart rate in some patients. The serotonin releaser/reuptakeinhibitors fenfluramine (Pondimin®) and dexfenfluramine (Redux™) havebeen reported to decrease food intake and body weight over a prolongedperiod (greater than 6 months). However, both products were withdrawnafter reports of preliminary evidence of heart valve abnormalitiesassociated with their use. There is therefore a need for the developmentof a safer anti-obesity agent.

The non-selective 5-HT_(2C) receptor agonists/partial agonistsm-chlorophenylpiperazine (mCPP) and trifluoromethylphenylpiperazine(TFMPP) have been shown to reduce food intake in rats (G. A. Kennett andG. Curzon, Psychopharmacol., 1988, 96, 93-100; G. A. Kennett, C. T.Dourish and G. Curzon, Eur. J. Pharmacol., 1987, 141, 429-435) and toaccelerate the appearance of the behavioural satiety sequence (S. J.Kitchener and C. T. Dourish, Psychopharmacol., 1994, 113, 369-377).Recent findings from studies with mCPP in normal human volunteers andobese subjects have also shown decreases in food intake. Thus, a singledose of mCPP decreased food intake in female volunteers (A. E. S. Walshet al., Psychopharmacol., 1994, 116, 120-122) and decreased the appetiteand body weight of obese male and female subjects during subchronictreatment for a 14 day period (P. A. Sargeant et al., Psychopharmacol.,1997, 133, 309-312). The anorectic action of mCPP is absent in 5-HT_(2C)receptor knockout mutant mice (L. H. Tecott et al., Nature, 1995, 374,542-546) and is antagonised by the 5-HT_(2C) receptor antagonistSB-242084 in rats (G. A. Kennett et al., Neuropharmacol., 1997, 36,609-620). It seems therefore that mCPP decreases food intake via anagonist action at the 5-HT_(2C) receptor.

Other compounds which have been proposed as 5-HT_(2C) receptor agonistsfor use in the treatment of obesity include the substituted 1-aminoethylindoles disclosed in EP-A-0655440. CA-2132887 and CA-2153937 disclosethat tricyclic 1-aminoethylpyrrole derivatives and tricyclic1-aminoethyl pyrazole derivatives bind to 5-HT_(2C) receptors and may beused in the treatment of obesity. WO-A-98/30548 disclosesaminoalkylindazole compounds as 5-HT_(2C) agonists for the treatment ofCNS diseases and appetite regulation disorders.2-(2,3-Dihydro-1H-pyrrolo[1,2-a]indol-9-yl)ethylamine is disclosed in J.Med. Chem., 1965, 8, 700. The preparation of pyrido[1,2-a]indoles forthe treatment of cerebrovascular disorders is disclosed in EP-A-0252643and EP-A-0167901. The preparation of10-[(acylamino)ethyl]tetrahydropyrido[1,2-a]indoles as anti-ischemicagents is disclosed in EP-A-0279125.

It is an object of this invention to provide selective, directly acting5HT₂ receptor ligands for use in therapy and particularly for use asanti-obesity agents. It is a further object of this invention to providedirectly acting ligands selective for 5-HT_(2B) and/or 5-HT_(2C)receptors, for use in therapy and particularly for use as anti-obesityagents. It is a further object of this invention to provide selective,directly acting 5-HT_(2C) receptor ligands, preferably 5-HT_(2C)receptor agonists, for use in therapy and particularly for use asanti-obesity agents.

SUMMARY OF INVENTION

The invention is concerned particularly with compounds of formula I andtheir pharmaceutically acceptable salts, solvates and esters

wherein

-   R¹, R², R³ and R⁴ are independently hydrogen, halogen, hydroxy,    alkyl, cycloalkyl, aralkyl, aryl, alkoxy, alkoxy alkyl, hydroxy    alkyl, alkoxy alkoxy alkyl, hydroxyalkoxy alkyl, halo alkyl, halo    alkoxy, aryloxy, alkylcarbonyl, arylcarbonyl, alkylthio, arylthio,    alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino,    nitro, cyano, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,    dialkylaminocarbonyl, alkylcarbonylamino, carboxy, heterocyclyl or    R³ and R⁴ form together with the carbon atoms to which they are    attached form a 5- to 7-membered carbocyclic ring which ring is    unsubstituted or alkyl substituted;-   R⁵ is hydrogen, alkyl or cycloalkyl;-   R⁶ is hydrogen, alkyl, hydroxy alkyl, carbamoyl alkyl,    alkoxycarbonyl alkyl, aryloxycarbonyl alkyl or —(CH₂)_(n)-A;-   R⁷ is hydrogen, alkyl, cycloalkyl, hydroxyalkyl or alkoxyalkyl,    whereby R⁷ is not hydrogen when R⁶ is hydrogen, alkyl, cycloalkyl or    1H-pyrrolo(2,3-b)pyridin-3-ylmethyl;-   R⁸ is hydrogen, alkyl or cycloalkyl;-   A is a heterocyclyl or cycloalkyl ring which ring can be    unsubstituted or substituted on a ring carbon atom with a hydroxy,    carboxy, oxo, alkanoyloxy alkyl, aryloxycarbonyl or alkylcarbamoyl    substituent;-   n is 0, 1, 2 or 3;    are selectively active 5-HT₂ receptor agonists for use in treating    obesity and in the use in treating Type I and Type II diabetes.

DETAILED DESCRIPTION

Among the preferred compounds of this invention are compounds of theformula

wherein

-   R¹², R¹³ and R¹⁴ are independently hydrogen, halogen,    trifluoromethyl, lower alkyl, lower alkoxy lower alkyl, lower    alkoxy-lower alkoxy lower alkyl, halo lower alkoxy, lower    alkyl-aminocarbonyl, di-lower alkyl aminocarbonyl or cyano and R¹⁷    is lower alkyl or hydroxy lower alkyl;-   compounds of the formula-   wherein one of R²² and R²³ is hydrogen and the other is hydroxy    lower alkyl, alkyl lower-alkylaminocarbonyl, di-lower    alkylaminocarbonyl, alkoxy lower alkyl, lower alkylcarbonylamino or    lower alkoxy-lower alkoxy lower alkyl; or-   R²² and R²³ taken together with the carbon atoms to which they are    added to form a 4- to 6-membered saturated carbocyclic ring which    ring is unsubstituted or lower alkyl substituted and-   R²⁷ is lower alkyl;-   and compounds of the formula    wherein-   R¹² R¹³ and R¹⁴ are independently hydrogen, halogen,    trifluoromethyl, lower alkyl, lower alkoxy lower alkyl, lower alkoxy    lower alkoxy lower alkyl, halo lower alkoxy, lower alkyl    aminocarbonyl or di-lower alkyl aminocarbonyl, cyano; R²⁷ is lower    alkyl or hydroxy-lower alkyl and-   R²⁶ is (CH₂)_(n)—Y, hydroxy lower alkyl, lower alkoxycarbonyl lower    alkyl or carbamoyl lower alkyl;-   Y is a saturated 3- to 6-membered carbocyclic ring or a 5- to    7-membered heterocyclic ring containing at most two hetero atoms    selected from the group consisting of oxygen, sulfur or nitrogen,    which rings can be unsubstituted or substituted on a ring carbon    atom with an oxo; and-   n is 0, 1,2 or 3.

The compounds of formula I were all active as 5-HT₂ receptor agonists asdetermined by the Assay Procedures A-D hereinafter described. In view ofthis activity, the compounds of this invention are active in treatingobesity and diseases related to obesity such as those mentionedhereinbefore and particularly diabetes including Type I and Type IIdiabetes.

In the present description the term “alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 8carbon atoms, preferably a straight or branched-chain alkyl group with1-4 carbon atoms. Examples of straight-chain and branched C₁-C₈ alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomericheptyls and the isomeric octyls, preferably methyl, ethyl, propyl andisopropyl. Particularly preferred are methyl and ethyl. The preferredalkyl groups are lower alkyl groups containing from 1 to 6 carbon atoms.

The term “cycloalkyl” or “carbocyclic” ring, alone or in combination,signifies a saturated cycloalkyl ring with 3 to 8, preferably 3 to 6carbon atoms and most preferably a cycloalkyl ring with 4 to 6 carbonatoms. Examples of C₃-C₈ cycloalkyl are cyclopropyl, methyl-cyclopropyl,dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl,methyl-cyclopentyl, cyclohexyl, methylcyclohexyl, dimethyl-cyclohexyl,cycloheptyl and cyclooctyl, preferably cyclopropyl and particularlycyclopentyl.

The term “alkoxy”, alone or in combination, signifies a group of theformula alkyl-O— in which the term “alkyl” has the previously givensignificance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec.butoxy and tert.butoxy, preferably methoxy and ethoxy.The preferred alkoxy group is a lower alkoxy group containing from 1 to6 carbon atoms.

The term “aryloxy”, alone or in combination, signifies a group of theformula aryl-O—. Phenyloxy is an example of such an aryloxy group. Thepreferred aryl group is phenyl.

The term “haloalkyl”, alone or in combination, signifies an alkyl groupas previously defined, with lower alky being preferred, wherein one orseveral hydrogen atoms, preferably one hydrogen atom have/has beenreplaced by halogen. Examples of haloalkyl groups are trifluoromethyl,pentafluoroethyl and trichloromethyl. Preferred examples aretrifluoromethyl and difluoromethyl.

The term “haloalkoxy”, alone or in combination, signifies an alkoxygroup, with lower alkoxy being preferred, as previously defined, whereinone or several hydrogen atoms, preferably one hydrogen atom have/hasbeen replaced by halogen. Examples of haloalkoxy groups aretrifluoromethoxy, pentafluoroethoxy and trichloromethoxy. A preferredexample is trifluoromethoxy.

The term “carbonyl” refer to a group of the formula —C(O)—. The termalkanoyl designates a monovalent alkanoyl substituent derived from analiphatic hydrocarbon carboxylic acids having the terminal hydroxy groupof the carboxylic acid moiety removed. The monovalent alkanoyl groupscontain from 2 to 10 carbon atoms with lower alkanoyl groups containingfrom 2 to 7 carbon atoms being preferred.

The term “alkylthio”, alone or in combination, signifies a group of theformula alkyl-S— in which the term “alkyl” has the previously givensignificance, such as methylthio, ethylthio, n-propylthio,isopropylthio. Preferred are methylthio and ethylthio.

The term “arylthio”, alone or in combination, signifies a group of theformula aryl-S— in which the term “aryl” has the previously givensignificance. Phenylthio is an example of such an arylthio group.

The term “sulphonyl”, alone or in combination, signifies a group of theformula

The term “sulfoxyl”, alone or in combination, signifies a group of theformula

The term “aryl”, alone or in combination, signifies a phenyl or naphthylgroup which optionally carries one to three substituents eachindependently selected from alkyl, alkoxy, halogen, carboxy,alkoxycarbonyl, aminocarbonyl, hydroxy, amino, nitro and the like, suchas phenyl, p-tolyl, 4-methoxyphenyl, 4-tert.butoxyphenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-hydroxyphenyl, 1-naphthyl and 2-naphthyl. Preferred are phenyl,4-fluorophenyl, 1-naphthyl and 2-naphthyl and particularly phenyl.

The term “heterocyclyl”, alone or in combination, signifies either asaturated 4- to 7-membered heterocyclic ring, partially unsaturated oraromatic 5- to 10-membered heterocycle, preferably a 5- or 6-memberedring. The heterocyclic ring can contain from one to three hetero atomsselected from nitrogen, oxygen and sulphur. Generally, such ringscontaining from one to 2 heteroatoms are preferred, with one heteroatombeing particularly preferred. If desired, they can be substituted on oneto three carbon atoms by halogen, alkyl, alkoxy, oxo etc. and/or on asecondary nitrogen atom (i.e. —NH—) by alkyl, cycloalkyl,aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiarynitrogen atom (i.e. ═N—) by oxido, with halogen, alkyl, cycloalkyl andalkoxy being preferred. Examples of such heterocyclyl groups arepyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,pyrazoyl, imidazoyl (e.g. imidazol-4-yl and1-benzyloxycarbonyl-imidazol-4-yl), pyrazoyl, pyridyl, pyrazinyl,pyrimidinyl, hexahydro-pyrimidinyl, furyl, thienyl, thiazolyl, oxazolyl,indolyl (e.g. 2-indolyl), quinolyl (e.g. 2-quinolyl, 3-quinolyl and1-oxido-2-quinolyl), isoquinolyl (e.g. 1-isoquinolyl and 3-isoquinolyl),tetrahydroquinolyl (e.g. 1,2,3,4-tetrahydro-2-quinolyl),1,2,3,4-tetrahydroisoquinolyl (e.g.1,2,3,4-tetrahydro-1-oxo-isoquinolyl) and quinoxalinyl. Preferred areoxazolidinone, cyclobutanonyl, [1,2,4]triazol-3-yl,[1,2,4]oxadiazol-3-yl, [1,2,4]triazol-3-one-5-yl, tetrazolyl,[1,3,4]oxadiazol-2-yl, [1,3,4]thiadiazol-2-yl, 1H-imidazol-2-yl,1H-imidazol-4-yl. Particularly preferred examples for heterocyclyl are[1,2,4]oxadiazol-3-yl or cyclobutanon-2-yl.

The term “amino”, alone or in combination, signifies a primary,secondary or tertiary amino group bonded via the nitrogen atom, with thesecondary amino group carrying an alkyl or cycloalkyl substituent andthe tertiary amino group carrying two similar or different alkyl orcycloalkyl substituents or the two nitrogen substitutents togetherforming a ring, such as, for example, —NH₂, methylamino, ethylamino,dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl orpiperidino etc., preferably amino, dimethylamino and diethylamino andparticularly primary amino.

The term “halogen” signifies fluorine, chlorine, bromine or iodine andpreferably fluorine, chlorine or bromine and particularly chlorine andbromine.

The term “carboxy”, alone or in combination, signifies a —COOH group.

The term “carboxyalkyl” alone or in combination, signifies an alkylgroup as previously described in which one hydrogen atom has beenreplaced by a carboxy group. The carboxymethyl group is preferred andparticularly carboxyethyl.

The term “carbamoyl” refers to a group of the formula amino-C(O)—.

The term “cycloalkanonyl” refers to a cycloalkyl ring, wherein onecarbon ring atom has been replaced by a —C(O)— group. In this manner,cycloalkanoyl designates a saturated carbocyclic ring which issubstituted on one ring carbon atom with an oxo group. Preferably, thering contains from 3 to 6 ring members and most perferably 4 to 6 ringmembers.

Compounds of formula I, wherein R³ and R⁴ form together with the carbonatoms to which they are attached a 5- to 7-membered carbocyclic ring,which is optionally substituted by alkyl comprise one of the followingmoieties IAA, IBB or ICC:

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition these salts may be preparedform addition of an inorganic base or an organic base to the free acid.Salts derived from an inorganic base include, but are not limited to,the sodium, potassium, lithium, ammonium, calcium, magnesium salts andthe like. Salts derived from organic bases include, but are not limitedto salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polymine resins and the like.The compound of formula I can also be present in the form ofzwitterions.

The invention expressly includes pharmaceutically acceptable salts,esters and solvates of compounds according to formula I which includescompounds of formulae I-A, I-B and I-C. The compounds of formula I canbe solvated, e.g. hydrated. The solvation can be effected in the courseof the manufacturing process or can take place e.g. as a consequence ofhygroscopic properties of an initially anhydrous compound of formula I(hydration). The term pharmaceutically acceptable salts also includesphysiologically acceptable solvates.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

In more detail, for example, the COOH groups of compounds according toformula I can be esterified. The alkyl and aralkyl esters are examplesof suitable esters. The methyl, ethyl, propyl, butyl and benzyl estersare preferred esters. The methyl and ethyl esters are especiallypreferred. Further examples of pharmaceutically usable esters arecompounds of formula I, wherein the hydroxy groups can be esterified.Examples of such esters are formate, acetate, propionate, butyrate,isobutyrate, valerate, 2-methylbutyrate, isovalerate andN,N-dimethylaminoacetate. Preferred esters are acetate andN,N-dimethylaminoacetate.

The term “lipase inhibitor” refers to compounds which are capable ofinhibiting the action of lipases, for example gastric and pancreaticlipases. For example orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also topolymer bound lipase inhibitors for example described in InternationalPatent Application WO99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterized in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds. The term“lipase inhibitor” preferably refers to orlistat.

Orlistat is a known compound useful for the control or prevention ofobesity and hyperlipidemia. See, U.S. Pat. No. 4,598,089, issued Jul. 1,1986, which also discloses processes for making orlistat and U.S. Pat.No. 6,004,996, which discloses appropriate pharmaceutical compositions.Further suitable pharmaceutical compositions are described for examplein International Patent Applications WO 00/09122 and WO 00/09123.Additional processes for the preparation of orlistat are disclosed inEuropean Patent Applications Publication Nos. 185,359, 189,577, 443,449,and 524,495.

Orlistat is preferably orally administered from 60 to 720 mg per day individed doses two to three times per day. Preferred is wherein from 180to 360 mg, most preferably 360 mg per day of a lipase inhibitor isadministered to a subject, preferably in divided doses two or,particularly, three times per day. The subject is preferably an obese oroverweight human, i.e. a human with a body mass index of 25 or greater.Generally, it is preferred that the lipase inhibitor be administeredwithin about one or two hours of ingestion of a meal containing fat.Generally, for administering a lipase inhibitor as defined above it ispreferred that treatment be administered to a human who has a strongfamily history of obesity and has obtained a body mass index of 25 orgreater.

Orlistat can be administered to humans in conventional oralcompositions, such as, tablets, coated tablets, hard and soft gelatincapsules, emulsions or suspensions. Examples of carriers which can beused for tablets, coated tablets, dragees and hard gelatin capsules arelactose, other sugars and sugar alcohols like sorbitol, mannitol,maltodextrin, or other fillers; surfactants like sodium lauryle sulfate,Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maizestarch or derivatives thereof; polymers like povidone, crospovidone;talc; stearic acid or its salts and the like. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Moreover, the pharmaceuticalpreparations can contain preserving agents, solubilizers, stabilizingagents, wetting agents, emulsifying agents, sweetening agents, coloringagents, flavoring agents, salts for varying the osmotic pressure,buffers, coating agents and antioxidants. They can also contain stillother therapeutically valuable substances. The formulations mayconveniently be presented in unit dosage form and may be prepared by anymethods known in the pharmaceutical art. Preferably, orlistat isadministered according to the formulation shown in the Examples and inU.S. Pat. No. 6,004,996, respectively.

The compounds of formula I can contain several asymmetric centres andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereioisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbens or eluent).

Preferred compounds according to formula I are those,

wherein

-   R¹, R², R³ and R⁴ are independently selected from hydrogen, halogen,    hydroxy, alkyl, cycloalkyl, aralkyl, aryl, alkoxy, alkoxyalkyl,    haloalkyl, aryloxy, alkylcarbonyl, arylcarbonyl, alkylthio,    arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl,    amino, nitro, cyano, alkoxycarbonyl, aryloxycarbonyl,    alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino,    carboxy or heterocyclyl;-   R⁵ is hydrogen, alkyl or cycloalkyl;-   R⁶ is hydrogen, alkyl, cycloalkyl, hydroxyalkyl, carbamoylalkyl,    alkoxycarbonylalkyl, aryloxycarbonylalkyl or —(CH₂)_(n)-A;-   R⁷ is hydrogen, alkyl or cycloalkyl, whereby R⁷ is not hydrogen when    R⁶ is hydrogen, alkyl, cycloalkyl or    1H-pyrrolo(2,3-b)pyridin-3-ylmethyl;-   R⁸ is hydrogen;-   A is heterocyclyl, cycloalkanonyl or cycloalkyl substituted with    hydroxy, carboxy, alkyloxycarbonyl, aryloxycarbonyl or carbamoyl;-   n is 0, 1, 2 or 3;    and their pharmaceutically usable salts, solvates and esters.

Preferred compounds according to formula I are those, wherein R¹, R², R³and R⁴ are independently selected from hydrogen, halogen, hydroxy,alkyl, cycloalkyl, aralkyl, aryl, alkoxy, alkoxyalkyl, haloalkyl,aryloxy, alkylcarbonyl, arylcarbonyl, alkylthio, arylthio,alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, nitro,cyano, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylcarbonylamino, carboxy or heterocyclyl. Alsopreferred are compounds according to formula I, wherein R³ and R⁴ formtogether with the carbon atoms to which they are attached a 5-memberedcarbocyclic ring otionally substituted by alkyl, wherein these compoundscompise the moiety of formula IA.

Further preferred compounds according to formula I are those, whereinR¹, R², R³ and R⁴ are independently selected from hydrogen, halogen,alkyl, alkoxy, haloalkyl, haloalkoxy and cyano. Particularly preferredcompounds of formula I are those, wherein one or two of R¹, R², R³ andR⁴ are independently selected from chloro, bromo, methyl,trifluoromethyl and cyano and the others are hydrogen.

Preferred compounds of formula I are those, wherein R⁵ is hydrogen,alkyl or cycloalkyl. Another preferred embodiment of the inventioncomprises compounds of formula I, wherein R⁵ is hydrogen or alkyl.Particularly preferred are compounds according to formula I, wherein R⁵is hydrogen.

Further preferred compounds according to formula I are those, wherein R⁶is hydrogen, alkyl, cycloalkyl, hydroxyalkyl, carbamoylalkyl,alkoxycarbonylalkyl, aryloxycarbonylalkyl or —(CH₂)_(n)-A. Particularlypreferred are those compounds of formula I, wherein R⁶ is hydrogen,hydroxyalkyl, carbamoylalkyl, alkyloxycarbonylalkyl or —(CH₂)_(n)-A.Very preferred are compounds of formula I, wherein R⁶ is hydrogen.

A further preferred embodiment of the present invention are thecompounds according to formula I, wherein A is oxazolidinone,cyclobutanonyl, [1,2,4]triazol-3-yl, [1,2,4]oxadiazol-3-yl,[1,2,4]triazol-3-one-5-yl, tetrazolyl, [1,3,4]oxadiazol-2-yl,[1,3,4]thiadiazol-2-yl, 1H-imidazol-2-yl or 1H-imidazol-4-yl.Particularly preferred are 2-oxazolidin-2-one and cyclobutanon-2-yl.

Moreover, preferred are those compounds, wherein A is cycloalkanoyl andn is 0. Likewise preferred are the compounds according to formula I,wherein A is heterocyclyl and n is 1.

Another preferred aspect of the present invention are compounds offormula I, wherein n is 0 or 1.

Among the preferred compounds of formula I-A are those where R¹² and R¹³are halo and R¹⁴ is hydrogen and R¹⁷ is lower alkyl, particularlymethyl. Another preferred embodiment of the compound of formula I-A arethose compounds where R¹² is halogen, R¹³ and R¹⁴ are hydrogen and R¹⁷is lower alkyl, particularly methyl or ethyl. Another embodiment of thecompound of formula I-A are those compounds where R¹², R¹³ and R¹⁴ arehalo, while R¹⁷ is lower alkyl, particularly methyl. Still anotherembodiment of the compound of formula I-A are those compounds where R¹²is hydrogen and R¹³ and R¹⁴ are independently hydrogen or lower alkyland R¹⁷ is lower alkyl, particularly methyl. Still another embodiment ofthe compounds of formula I-A are those compounds where R¹² is hydrogenand R¹³ and R¹⁴ are halo or lower alkyl, while R¹⁷ is lower alkyl,particularly methyl. While R¹⁷ is lower alkyl, particularly methyl, astill further embodiment of the compound of formula I-A are thosecompounds where R¹² is hydrogen and one of R¹³ and R¹⁴ is trimethyl,trifluoromethoxy or cyano while the other is hydrogen halo or loweralkyl and R¹⁷ is lower alkyl, particularly methyl. Another embodiment ofthe compound of formula I-A are those where R¹⁷ is hydroxy lower alkylwhile R¹² is hydrogen and one of R¹³ and R¹⁴ is trifluoromethyl,trifluoromethoxy or cyano while the other is hydrogen, halo or loweralkyl.

The compound of formula I-B has various preferred embodiments. Among thepreferred embodiments are those compounds where R²² and R²³ takentogether with their attached carbon atoms form a carbocyclic ring,particularly the 4 to 6 membered saturated carbocyclic ring. Anotherembodiment of the compound of formula I-B are those compounds whereinone of R²² and R²³ is hydrogen while the other is hydroxy, lower alkyllower alkyl aminocarbonyl, di-lower alkyl amino carbonyl, lower alkoxylower alkyl, lower alkylcarbonylamino or lower alkoxy lower alkoxy loweralkyl.

Preferred embodiments are where Y is a saturated 4 to 6 memberedcarboxylic ring or is a 5 to 7 membered heterocyclic ring containing atmost two heteroaotms selected from the group consisting of oxygen ornitrogen. Generally, the compounds of formula I-C were Y is aheterocyclic ring containing either one oxygen or one nitrogen atom inthe ring are generally preferred.

Preferred compounds according to formula I are those, wherein R⁷ ishydrogen or alkyl. Particularly preferred are methyl and ethyl.

Further preferred compounds according to formula I are those, wherein R⁸is hydrogen or alkyl. Particularly preferred are compounds of formula I,wherein R⁸ is methyl. Very preferred are compounds according to formulaI, wherein R⁸ is hydrogen.

Examples of preferred compounds of formula I are:

-   (2S,10aR)-2-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-cyclobutanone;-   (2R,10aR)-2-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-cyclobutanone;-   (2S,10aS)-2-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-cyclobutanone;-   (2R,10aS)-2-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-cyclobutanone;-   (10aR)-3-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-ylmethyl)-oxazolidin-2-one;-   (10aS)-3-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-ylmethyl)-oxazolidin-2-one;-   (10aR)-2-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-ethanol;-   (10aR)-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-acetic    acid methyl ester;-   (10aR)-2-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-acetamide;-   (4R,10aR)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4S,10aS)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4S,10aR)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole.-   (4R,10aR)-4-Methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-4-Methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-6-Ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-6-Ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-8-Bromo-4-methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4,6,7-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Bromo-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4,8-Dimethyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-9-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-4,8-Dimethyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Chloro-8-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-8-Bromo-4-methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-7-carbonitrile;-   (4R,10aR)-9-Chloro-6-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-6,7-Difluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-6,7-Difluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Chloro-6-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4RS,10aRS)-7-Bromo-4-ethyl-1,2,3,4,    10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4RS,10aSR)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4RS,10aRS)-6,7,8-Tribromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4RS,10aRS)-7,8-Dibromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4S,10aS)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4RS,10aSR)-4-Ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4RS,10aRS)-4-Ethyl-1,2,3,4, 10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-8-Bromo-6-ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10S,10aR)-4,6,10-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10R,10aR)-4,6,10-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-8-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-8-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-6-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-6-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-8-Fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4,6-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-4,6-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Bromo-9-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-6-Fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-6,9-Difluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7,9-Dichloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-7,9-Dichloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4,7,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-6-Bromo-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Fluoro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-7-Chloro-4,8-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Chloro-4,8-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4-Methyl-6-trifluoromethoxy-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-6-Fluoro-4,9-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]in    dole;-   (4R,10aS)-6-Fluoro-4,9-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-6-carbonitrile;-   (4R,10aR)-6-Chloro-48-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indo    le;-   (4R,10aS)-6-Chloro-4,8-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4,6,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-4,6,7-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-4,6,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Chloro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-7-Chloro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4S,10aS)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4S,10aR)-7-chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-7-chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4S,10aS)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4S,10aR)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-6-Chloro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-6-Chloro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (10R,6aS)-10-Methyl-2,3,6,6a,7,8,9,10-octahydro-1H-8,10a-diaza-cyclopenta[c]fluorene;-   (4R,10aR)-N-(4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-7-yl)-acetamide;-   (4R,10aR)-(4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-7-yl)-methanol;-   (4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-7-carboxylic    acid butylamide;-   (4R,10aR)-4,8-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-8-Bromo-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-8-Bromo-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)4,7-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)4,7-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4,7,8-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)    4,7,8-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-6,7-Dichloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-8-Fluoro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-8-Bromo-7-fluoro-4methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-8-Bromo-7-fluoro-4methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-7-carboxylic    acid diethylamide;-   (4R,10aR)-8-Fluoro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Methoxymethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-(2-Methoxy-ethoxymethyl)-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-6-Bromo-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4S,10aS)-(7-Trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-4-yl)-methanol;    and-   (4S,10aR)-(7-Trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-4-yl)-methanol.

Examples of particularly preferred compounds of formula I are:

-   (4R,10aR)-7-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4,6,7-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Bromo-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4,8-Dimethyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4,6-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-6-carbonitrile;-   (4R,10aS)-4,6,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R,10aS)-7-Chloro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;    and-   (4R,10aS)-6-Chloro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole.

Processes for the manufacture of the compounds according to formula Iare an object of the present invention. The substituents and indicesused in the following schemes have the significance given above unlessindicated to the contrary.

Indoles of formula A can be prepared by methods known in the art, (e.g.,T. L. Gilchrist, Heterocyclic chemistry, 1997 or The chemistry ofheterocyclic compounds Vol 25, 1972 or Joule, J. A. Indoles, isoindoles,their reduced derivatives, and carbazoles. Rodd's Chem. Carbon Compd.1997 or G. W. Gribble, J. Chem. Soc. Perkin 12000, 1045)

Indole-2-carboxylates of formula B can be prepared by methods known inthe art (see above) or alternatively from indoles of formula A by firstprotecting the indole nitrogen with a suitable protecting group (PG;e.g., tert-butoxycarbonyl (Boc)), treating the protected indolederivative with a suitable base under anhydrous conditions (e.g., withlithium 2,2,6,6-tetramethylpiperidide in THF), reacting the intermediateanion with a chloroformate (e.g. ethyl chloroformate) and removing theprotecting group (e.g., by treatment with acid for the Boc protectinggroup). Ra in scheme 1 is an alkyl group, preferably methyl or ethyl.

Pyrazinoindoles of formula D1 can be prepared by a process where theindole-2-carboxylate of formula B is first reacted with an alpha haloalkanenitrile (e.g., 2-bromo propionitrile) in a suitable solvent (e.g.,DMF) with a suitable base (e.g., NaH). The intermediate C is reduced andcyclized to the tetrahydro-pyrazino[1,2-a]indole D1 by reaction with asuitable reducing agent in a suitable solvent (e.g., LiAlH₄ in THF ordiethylether). In the case where R⁷≠H, the latter reduction ispreferably carried out stepwise, by subsequent treatment of intermediateC with (i) borane-dimethylsulfide complex in THF, (ii) potassiumcarbonate in methanol, (iii) borane-dimethylsulfide complex in THF.R^(b) in scheme 2 is an alkyl group, preferably a lower alkyl group,preferably methyl or ethyl.

Pyrazinoindoles of formula D1 can also be prepared by a process wherethe indole-2-carboxylate of formula B is first reacted with the hithertounknown Boc-sulfamidate (II) in a suitable solvent (e.g., DMF or2-methyl-2-butanol) with a suitable base (e.g., potassium tert-butylateor sodium hydride) followed by removal of the Boc protecting group andring closure in the presence of base (e.g., potassium carbonate). Thestereochemistry of the carbon atom attached to R⁷ in Boc-sulfamidate IIis inverted (>90% e.e.) in this reaction sequence. The intermediateamide (E1) is reduced with a suitable reducing agent in a suitablesolvent (e.g., LiAlH₄ in diethyl ether or borane-dimethylsulfide complexin THF). R^(a) in Scheme 3 is an alkyl group, preferably a lower alkylgroup, preferably methyl or ethyl.

If racemic Boc-sulfamidate II is used in this process, the enantiomersof intermediate E1 can be obtained, e.g., by preparative chiral HPLC asdepicted in scheme 4.

Intermediate E1 can also be prepared by a multi-step procedure startingwith saponification of the ester B (e.g., with LiOH in THF/watermixtures) to the indole-2-carboxylic acid, amide coupling of the acidwith a suitable aminoalcohol derivative (PG is a suitable protectinggroup, e.g., benzyl), transformation of the hydroxyl into a leavinggroup (e.g., with mesylchloride), treatment with a suitable base in asuitable solvent (e.g., NaH in DMF), and cleavage of the protectivegroup (e.g., by hydrogenation in the presence of a palladium catalyst oncarbon in the case of PG=benzyl). R^(c) in scheme 5 is an alkyl group,preferably a lower alkyl group, preferably methyl or ethyl.

Intermediate E2 can also be prepared according to scheme 6, by a processwhere indole-2-carboxylate B is first reacted with an activatedaminoethanol derivative (e.g. Boc-aziridine in a suitable solvent e.g.DMSO with a suitable base, e.g., KOH) followed by removal of the Bocprotecting group and ring closure in the presence of base (e.g.,potassium carbonate).

Indole derivatives F can be prepared starting from protectedo-iodoanilines (a suitable protective group, PG¹, is, N-methoxycarbonyl)by reaction with suitably substituted and optionally protected carbinols(preferred protective groups are silyl ethers, especially preferred istert-butyl-dimethylsilyl). The reaction proceeds in the presence of asuitable catalyst (e.g.; bis-triphenylphosphine palladium dichloride andcopper(I)iodide as co-catalyst) in a suitable solvent (e.g.triethylamine). The intermediate is treated with a base (e.g. LiOH inTHF/water) to yield the indole derivative F1 (scheme 7).

Intermediates of formula G can be prepared according to scheme 8 by aprocess where the indole derivative of formula F2 is first reacted withthe hitherto unknown Boc-sulfamidate (II) in a suitable solvent (e.g.,DMF or 2-methyl-2-butanol) with a suitable base (e.g., NaH or potassiumtert-butylate) followed by deprotection of the alcohol (e.g., withtetrabutylammoniumfluoride) in a solvent (e.g., THF) and oxidation ofthe alcohol (e.g., with manganese dioxide). The stereochemistry of thecarbon atom attached to R⁷ in Boc-sulfamidate II is inverted (>90% e.e.)in this reaction sequence.

Indole derivatives G can also be prepared according to scheme 9,starting from protected o-iodoanilines (a suitable protective group,PG¹, is, N-methoxycarbonyl) by cross-coupling reaction with propargylalcohol derivatives in the presence of a suitable catalyst (e.g.,bis-triphenylphosphine palladium dichloride and copper(I)iodide asco-catalyst) in a suitable solvent (e.g. triethylamine), followed bytreatment with a base (e.g. LiOH in THF/water). The alcohol intermediateis oxidised, e.g., with manganese dioxide, to yield the indolederivative H. Alkylation of H with Boc-sulfamidate (II) in a suitablesolvent (e.g., DMF or 2-methyl-2-butanol) with a suitable base (e.g.,potassium tert-butylate or NaH) leads to intermediate G. Thestereochemistry of the carbon atom attached to R⁷ in Boc-sulfamidate IIis inverted (>90% e.e.) in this reaction.

These intermediates of formula G can be further processed to compoundsof formula D2 by either removal of the Boc protecting group (e.g., withtrifluoroacetic acid) to yield an imine intermediate which is notisolated but reduced directly with lithium aluminium hydride to yield D2as a separable mixture of epimers, or direct reductive amination (e.g.,with sodium triacetoxyborohydride, molecular sieves and acetic acid in asuitable solvent, e.g., dichloromethane) followed deprotection of theintermediate J1 (e.g., with trifluoroacetic acid in dichloromethane) asdepicted in scheme 10.

Substituents R⁸ can be introduced as shown in scheme 11, starting fromtetrahydropyrazino[1,2-a]indole D3. To that end, the amine nitrogen ofD3 is protected, e.g., as the tert-butyl carbamate to generate compoundJ2, which is elaborated as follows:

-   a) Vilsmeier reaction yields aldehyde K, which is be reduced to    tetrahydropyrazino[1,2-a]indole D4, preferably with triethylsilane    in trifluoroacetic acid.-   b) Halogenation (preferably with N-iodosuccinimide or    N-bromosuccinimide in acetonitrile) yields halide L, which is    transformed into compound J1 by cross-coupling reaction, using    methods known in the art (e.g., F. Diederich, P. J. Stang (eds.),    Metal-catalyzed Cross-coupling Reactions, Wiley-VCH, 1998)

The enantiomers of tetrahydropyrazino[1,2-a]indoles D1 can be obtainedeither by using a chiral sulfamidate (II) or by separation of theenantiomers by preparative chiral HPLC or by crystallisation withsuitable chiral acids, separation of the diastereomeric salts andisolation of the enantiomers from these salts (scheme 12). Analternative access to the enantiomers of tetrahydro-pyrazinoindoles D1involves the separation of the enantiomers of the precursors C or G,e.g., by preparative chiral HPLC.

The hexahydro-pyrazino[1,2-a]indoles of formula IA can be prepared fromcompounds of formula D2 by reduction with suitable reducing agents (e.g.NaBH₄) in suitable solvents or solvent mixtures, e.g., THF/TFA (scheme13)

Hexahydro-pyrazino[1.2-a]indoles of formula IB can also be prepared in atwo-step process from intermediate E1 where the indole moiety is reducedto produced indoline-amide M, which is then reduced under suitableconditions, e.g., LiAlH₄ in diethyl ether (scheme 14).

Functional groups R¹ to R⁴ that do not tolerate the methods describedfor the pyrazino-indole synthesis can be prepared from such functionalgroups that do by methods known in the art (e.g. March, Advanced OrganicChemistry 4^(th) edition or Comprehensive Organic Functional GroupTransformations, 1995). In particular, the transformations outlined inscheme 15 are carried out starting from the protected bromide N (asuitable protective group, PG, is tert-butoxycarbonyl, which isintroduced by standard methods; R are one or two non-interferingsubstituents):

-   a) Cross-coupling reaction with benzophenone imine using a palladium    catalyst and an auxilliary ligand, e.g., 2,2′-bis(diphenylphosphino)    1,1′-binaphthyl (BINAP) and subsequent hydrogenation reaction,    yields amine P, which then is acylated with acid chloride R¹¹COCl    (R¹¹=alkyl) to produce amide Q.-   b) Cross-coupling reaction with copper cyanide using a palladium    catalyst and an auxilliary ligand, e.g.,    1,1′-Bis(diphenylphosphino)ferrocene (dppf), yields nitrile R.-   c) Lithiation with n-BuLi in THF and subsequent treatment with    carbon dioxide affords carboxylic acid S, which is    -   c1) coupled with an amine R¹²—NH—R¹² (R¹²=H, alkyl) in the        presence of a coupling agent, e.g.,        benzotriazol-1-yl-oxytris(dimethylamino)phosphonium        hexafluorophosphate (BOP) and a base, e.g., 4-ethylmorpholine,        to yield amide T, or,    -   c2) reduced (e.g., with lithium aluminumhydride in THF) to        produce alcohol U, which then is alkylated with halide R¹³X        (R³=alkyl, alkoxyalkyl, X=leaving group, e g., Br, I) to afford        aryl ether V.

Cleavage of the protective group in compounds P, Q, R, S, T, U, or V(e.g., with acid such as trifluoroacetic acid or hydrogen chloride in asuitable solvent such as ethyl acetate in the case of PG=Boc) yieldshexahydro-pyrazino[1,2-a]indoles IA (scheme 16).

The hexahydro-pyrazino[1.2-a]indoles of formula I can be prepared fromcompounds of formula IA by methods known in the art (e.g. March,Advanced Organic Chemistry, 4th. edition, page 411ff, 768ff, 898ff,900ff, 1212ff.) e.g., alkylation reactions, Mannich reactions, acylationfollowed by reduction etc. (scheme 17).

The hitherto unknown Boc-sulfamidate II can be prepared according toscheme 18, by treating a Boc-protected ethanolamine derivatives withthionylchloride in a suitable solvent e.g. THF or ethyl acetate in thepresence of a suitable base, e.g. triethylamine or imidazole, andoxidising the intermediate (e.g., with sodium metaperiodate andruthenium(IV)oxide) in a suitable solvent (e.g., ethyl acetate). Thestereochemistry of the carbon atom attached to R⁷ remains unchanged(e.e. >97%) over this sequence. In the case where R⁷=hydroxyalkyl, thehydroxyl is protected with a suitable protective group, preferably asilyl ether, most preferably adimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl ether. Thedimethyl-(1,1,2-trimethylpropyl)-silanyloxymethyl ether is preferablydeprotected during the conversion of intermediates C or E1 totetrahydropyrazino[1,2-a]indole D1, by reaction with lithium aluminumhydride.

The compounds of formula (I) may be used in the treatment (includingprophylactic treatment) of disorders associated with 5-HT₂ receptorfunction. The compounds may act as receptor agonists or antagonists.Preferably, the compounds may be used in the treatment (includingprophylactic treatment) of disorders associated with 5-HT_(2B) and/or5-HT_(2C) receptor function. Preferably, the compounds may be used inthe treatment (including prophylactic treatment) of disorders where a5-HT_(2C) receptor agonist is required.

The compounds of formula (I) may be used in the treatment or preventionof central nervous disorders such as depression, a typical depression,bipolar disorders, anxiety disorders, obsessive-compulsive disorders,social phobias or panic states, sleep disorders, sexual dysfunction,psychoses, schizophrenia, migraine and other conditions associated withcephalic pain or other pain, raised intracranial pressure, epilepsy,personality disorders, age-related behavioural disorders, behaviouraldisorders associated with dementia, organic mental disorders, mentaldisorders in childhood, aggressivity, age-related memory disorders,chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia,anorexia nervosa or premenstrual tension; damage of the central nervoussystem such as by trauma, stroke, neurodegenerative diseases or toxic orinfective CNS diseases such as encephalitis or meningitis;cardiovascular disorders such as thrombosis; gastrointestinal disorderssuch as dysfunction of gastrointestinal motility; diabetes insipidus;and sleep apnea.

A further aspect of the invention is a compound according to formula Ifor use as therapeutically active substance.

According to an other aspect of the present invention, there is providedthe use of a compound of formula (I) in the manufacture of a medicamentcomprising a compound according to formula I for the treatment ofdisorders of the central nervous system, damage to the central nervoussystem, cardiovascular disorders, gastrointestinal disorders, diabetesinsipidus, and sleep apnea.

According to a preferred aspect of this invention the disorders of thecentral nervous system are selected from depression, a typicaldepression, bipolar disorders, anxiety disorders, obsessive-compulsivedisorders, social phobias or panic states, sleep disorders, sexualdysfunction, psychoses, schizophrenia, migraine and other conditionsassociated with cephalic pain or other pain, raised intracranialpressure, epilepsy, personality disorders, age-related behaviouraldisorders, behavioural disorders associated with dementia, organicmental disorders, mental disorders in childhood, aggressivity,age-related memory disorders, chronic fatigue syndrome, drug and alcoholaddiction, obesity, bulimia, anorexia nervosa and premenstrual tension.

According to a preferred aspect of this invention the damage to thecentral nervous system is by trauma, stroke, neurodegenerative diseasesor toxic or infective CNS diseases, particularly wherein the toxic orinfective CNS disease is encephalitis or meningitis.

A further preferred embodiment of the present invention is the abovementioned use, wherein the cardiovascular disorder is thrombosis.

Also preferred is the mentioned use of the compounds according toformula I, wherein the gastrointestinal disorder is dysfunction ofgastrointestinal motility.

Further preferred is the use of a compound of formula I in themanufacture of a medicament comprising a compound of formula I for thetreatment of diabetes.

Particularly preferred is the use of a compound of formula I in themanufacture of a medicament comprising a compound of formula I for thetreatment of obesity.

Further preferred is a method of treatment of any of the above mentioneddisorders comprising administering to a patient in need of suchtreatment an effective dose of a compound of formula (I). Also preferredis the use or method as mentioned before, wherein said treatment isprophylactic treatment.

A further preferred embodiment of the present invention is a process forthe preparation of a compound of formula I, wherein R¹ to R⁸ are definedas before, R^(b) is alkyl and PG means a protecting group, comprisingany one of the following steps:

-   a) preparation of a compound according to formula D1 by reacting a    compound of formula C in the presence of a reducing agent,    particularly preferred in the presence of lithium aluminium hydride;    or-   b) preparation of a compound according to formula E1 by reacting a    compound according to formula D1 in the presence of a reducing    agent, particularly preferred in the presence of lithium aluminium    hydride or borane-dimethylsulfide-complex; or-   c) preparation of a compound according to formula D2 by deprotection    of a compound according to formula J2. Particularly preferred    protecting groups (PG) are those, where N-PG signifies a carbamate    or amide group. In a preferred embodiment deprotection can be    performed as follows: a compound of formula J2, where PG is equal to    Boc is deprotected with a mixture of dichloromethane and    trifluoroacetic acid at room temperature; or-   d) preparation of a compound according to formula IA by reacting a    compound of formula D2 in the presence of a reducing agent,    particularly preferred in the presence of sodium borohydride in a    mixture of tetrahydrofuran and trifluoroacetic acid; or-   e) preparation of a compound according to formula IB by reacting a    compound of formula M in the presence of a reducing agent,    particularly preferred in the presence of lithium aluminum hydride;    or-   f) preparation of a compound according to formula I by reacting a    compound of formula IA in the presence of an alkylation or acylation    agent where acylation is followed by a reduction step.

Alkylation agent means alkyl- or cycloakyl-halogenides, functionalisedalkylhalogenides like hydroxylkylhalogenides, carbamoylhalogenides,alkoxycarbonylhalogenides, aryloxycarbonylalkylhalogenides orheterocyclylalkylhalogenides or the respective mesylates, tosylates ortriflates instead of the halogenides. Examples of alkylation agents are2-(bromoethoxy)-tert-butyl-dimethylsilane, methyl bromoacetate and2-bromoacetamide. Acylation agent means the activated derivatives (e.g.acid chlorides) of alkyl- or cycloalkyl-carboxylic acids,heterocyclylcarboxylic acids or heterocyclylalkylcarboxylic acids.Examples of acylation agents are acetyl chloride andcyclopropylcarboxylic acid chloride; or

-   g) preparation of a compound according to formula I by reacting a    compound of formula B, wherein R^(a) is alkyl in the presence of a    compound of formula (II), wherein PG is a protective group    preferably tert-butoycarbonyl (Boc);-    or-   h) preparation of a compound according to formula I by reacting a    compound of formula F2 in the presence of a compound of formula (II)    as defined before,-    wherein PG′ is hydrogen or an OH-protecting group preferably    trimethylsilyl, tert-butyldimethylsilyl, acetyl, methoxymethyl or    2-tetrahydropyranyl; or-   i) preparation of a compound according to formula I by reacting a    compound of formula H in the presence of a compound of formula (II)    as defined before

Another preferred aspect of this invention are the followingintermediates:

-   (R)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (S)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;-   (4R)-7-Chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2a]-indole and-   (4S)-7-chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2a]-indole.

Particularly preferred intermediates are:

-   (S)-5-Methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid    tert-butyl ester-   (RS)-5-Ethyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid    tert-butyl ester-   2,2-Dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester-   (R)-5-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic    acid tert-butyl ester.

According to a further aspect of the invention there is provided apharmaceutical composition comprising a compound of formula (I) incombination with a pharmaceutically acceptable carrier or excipient anda method of making such a composition comprising combining a compound offormula (I) with a pharmaceutically acceptable carrier or excipient.

A further aspect of the present invention is the above pharmaceuticalcomposition comprising further a therapeutically effective amount of alipase inhibitor. Particularly preferred is the above pharmaceuticalcomposition, wherein the lipase inhibitor is orlistat.

According to a further aspect of the invention there is provided amethod of treatment of obesity in a human in need of such treatmentwhich comprises administration to the human a therapeutically effectiveamount of a compound according to formula I and a therapeuticallyeffective amount of a lipase inhibitor, particularly preferred, whereinthe lipase inhibitor is orlistat. Also subject of the present inventionis the mentioned method, wherein the administration is simultaneous,separate or sequential.

A further preferred embodiment of the present invention is the use of acompound of the formula I in the manufacture of a medicament for thetreatment and prevention of obesity in a patient who is also receivingtreatment with a lipase inhibitor, particularly preferred, wherein thelipase inhibitor is orlistat.

The processes as described above may be carried out to give a compoundof the invention in the form of a free base or as an acid addition salt.If the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acidaddition salt. Conversely, if the product of the process is a free base,an acid addition salt, particularly a pharmaceutically acceptable acidaddition salt, may be obtained by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts frombasic compounds.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Thus, the active compounds of the invention may be formulatedfor oral, buccal, intranasal, parenteral (e.g., intravenous,intramuscular or subcutaneous) transdermal or rectal administration orin a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone orhydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystallinecellulose or calcium phosphate); lubricants (e.g. magnesium stearate,talc or silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulfate). The tabletsmay be coated by methods well known in the art. Liquid preparations fororal administration may take the form of, for example, solutions, syrupsor suspensions, or they may be presented as a dry product forconstitution with water or other suitable vehicle before use. Suchliquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, methyl cellulose or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters or ethyl alcohol); and preservatives (e.g.methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

The active compounds of the invention may be formulated for parenteraladministration by injection, including using conventionalcatheterization techniques or infusion. Formulations for injection maybe presented in unit dosage form e.g. in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulating agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form for reconstitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g., containingconventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, theactive compounds of the invention are conveniently delivered in the formof a solution or suspension from a pump spray container that is squeezedor pumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of the activecompound. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound of the invention and a suitable powder base such aslactose or starch.

A proposed dose of the active compounds of the invention for oral,parenteral or buccal administration to the average adult human for thetreatment of the conditions referred to above (e.g., obesity) is 0.1 to500 mg of the active ingredient per unit dose which could beadministered, for example, 1 to 4 times per day.

The invention will now be described in detail with reference to thefollowing examples. It will be appreciated that the invention isdescribed by way of example only and modification of detail may be madewithout departing from the scope of the invention.

Assay Procedures

1. Binding to Serotonin Receptors

The binding of compounds of formula (I) to serotonin receptors wasdetermined in vitro by standard methods. The preparations wereinvestigated in accordance with the assays given hereinafter.

Method (a): For the binding to the 5-HT_(2C) receptor the 5-HT_(2C)receptors were radiolabeled with [³H]-5-HT. The affinity of thecompounds for 5-HT_(2C) receptors in a CHO cell line was determinedaccording to the procedure of D. Hoyer, G. Engel and H. O. Kalkman,European J. Pharmacol., 1985, 118, 13-23.

Method (b): For the binding to the 5-HT_(2B) receptor the 5-HT_(2B)receptors were radiolabeled with [³H]-5-HT. The affinity of thecompounds for human 5-HT_(2B) receptors in a CHO cell line wasdetermined according to the procedure of K. Schmuck, C. Ullmer, P.Engels and H. Lubbert, FEBS Lett., 1994, 342, 85-90.

Method (c): For the binding to the 5-HT_(2A) receptor the 5-HT_(2A)receptors were radiolabeled with [¹²⁵I]-DOI. The affinity of thecompounds for 5-HT_(2A) receptors in a CHO cell line was determinedaccording to the procedure of D. J. McKenna and S. J. Peroutka, J.Neurosci., 1989, 9, 3482-90.

The thus determined activity of the compound of the Example is shown inTable 1.

TABLE 1 Method (a) Method (b) Method (c) Compound Ki (2C) Ki (2B) Ki(2A) Example 3 26 nM 110 230

Preferred compounds of formula I as described above have Ki (2C) valuesbelow 10000 nM; especially preferred compounds have Ki (2C) values below1000 nM, particularly preferred compounds have Ki (2C) values below 100nM. Most preferred compounds have Ki (2C) values below 30 nM.

2. Functional Activity

The functional activity of compounds of formula (I) was assayed using aFluorimetric Imaging Plate reader (FLIPR). CHO cells expressing thehuman 5-HT_(2C) or human 5-HT_(2A) receptors were counted and platedinto standard 96 well microtitre plates on the day before testing togive a confluent monolayer. The cells were then dye loaded with thecalcium sensitive dye, Fluo-3-AM. Unincorporated dye was removed usingan automated cell washer to leave a total volume of 100 μL/well of assaybuffer (Hanks balanced salt solution containing 20 mM Hepes and 2.5 mMprobenecid). The drug (dissolved in 50 μL of the assay buffer) was addedat a rate of 70 μL/sec to each well of the FLIPR 96 well plate duringfluorescence measurements. The measurements were taken at 1 secintervals and the maximum fluorescent signal was measured (approx 10-15secs after drug addition) and compared with the response produced by 10μM 5-HT (defined as 100%) to which it was expressed as a percentageresponse (relative efficacy). Dose response curves were constructedusing Graphpad Prism (Graph Software Inc.).

TABLE 2 h5-HT_(2c) h5-HT_(2A) h5-HT_(2B) EC₅₀ Relative EC₅₀ RelativeEC₅₀ Relative Compound (nM) Efficacy (%) (nM) Efficacy (%) (nM) Efficacy(%) Example 8 0.4 nM 97% 19 nM 60% 3.4 nM 62%

The compounds of formula (I) have activity at the h5-HT2c receptor inthe range of 10,000 to 0.01 nM.

Preferred compounds of formula I as described above have activity at theh5-HT2c receptor below 10000 nM; especially preferred compounds below1000 nM, particularly preferred compounds below 100 nM. Most preferredcompounds have activity at the h5-HT2c receptor below 30 nM.

3. Efficacy

The efficacy of 5-HT_(2c) agonists was assessed for ability to induce aspecific syndrome.

The 5-HT_(2c) syndrome is a rapid screening method to asses the in vivoefficacy of 5-TH_(2c) agonists through their ability to induce threespecific behaviours in rats. The animals are dosed with either apositive control (mCPP), test compound or vehicle, either s.c. or p.o.The animals are observed on an open bench, typically 30, 60 and 180minutes and the degree of syndrome is assessed over a two minute periodon a scale of 0-3 depending on the presence and severity of splayedlimbs, hunched posture and retro-pulsion, the three specific behaviourswhich constitute the syndrome. Data is analysed using Kruskal-WallisAnalysis of Variance followed with appropriate post-hoc tests. Allstatistical analysis are conducted using Excel version 7-0 (MicrosoftCorp.) and Statistica version 5.0 (Stasoft, Inc.).

The thus determined activity of the Example indicated that after a doseof 1 mg/kg s.c. the compound maintains a significant pharmacologicalefficacy for at least 180 minutes.

4. Regulation of Feeding Behaviour

The in vivo activity of compounds of formula (1) was assayed for abilityto regulate feeding behaviour by assaying food consumption in fooddeprived animals as follows.

Test compounds are assessed following acute administration. Each studyutilises a between-subjects design (typically n=8) and compares theeffects of doses of the test agent to those of vehicle and a positivecontrol.

The anorectic drug d-fenfluramine normally serves as a positive control.The route of drug administration, drug volume andinjection-test-interval are dependent upon the compounds used. Apalatable wet mash, made by adding powdered lab chow and water in aration of 1:2 and mixing to a smooth consistency, is presented in 120 mLglass jars for 60 minutes each day. Intake is measured by weighingbefore and after each session. Care is taken to collect all spillage.Animals are allowed to habituate to the wet mash meal for 10 days. Afterdrug administration, animals are allowed to consume the wet mash. Foodconsumption is assayed at pre-determined time points (typically, 1, 2and 4 hours after administration). Food intake data are subjected toone-way analysis of variance (ANOVA) with drug as a between-subjectsfactor. A significant main effect is followed up by the performance ofDunnett's test in order to asses which treatment mean(s) aresignificantly different from the control mean. All statistical analyseswere performed using Statistica Software, Version 5.0 (Statsofr Inc.)and Microsoft Excel 7.0 (Microsoft Corp.).

The thus determined activity of the Example indicated that the compoundsmaintain significant hypophagia 3 hours after a dose of 1 mg/kg s.c.

EXAMPLES Example 1 Mixture of (2S,10aR) and(2R,10aR)-2-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-cyclobutanone

(10aR)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (0.10 g,0.39 mmol) was suspended in methanol (1.5 mL). A solution of[1-cyclobutene-1,2-diylbis(oxy)]bis[trimethyl-silane, (0.10 g, 0.43mmol) in methanol (0.5 mL) was added, the mixture was stirred for 1 dand the solvent was evaporated. Chromatography on silica gel(dichloromethane/methanol 99:1) yielded the desired product (78 mg,61%), MS: m/e=321.3 (M⁺).

Example 2 Mixture of (2S,10aS) and (2R,10aS)-2-(9-bromo-3,4,10,1a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-cyclobutanone

The title compound, MS: m/e=321.2 (M⁺), was prepared in accordance withthe general method of example 1 from(10aS)-9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole and[1-cyclobutene-1,2-diylbis(oxy)]bis[trimethyl-silane.

Example 3(10aR)-3-(9-Bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-ylmethyl)-oxazolidin-2-one

(10aR)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (0.10 g,0.39 mmol) and 2-oxazolidinone (34 mg, 0.43 mmol) were dissolved indichloromethane (5 mL). Formaldehyde (32 μL of a 36.5% solution inwater) was added and the solution was stirred for 3 h at roomtemperature. The solvent was removed after drying with MgSO₄.Chromatography on silica gel (dichloromethane/ethylacetate 3:1) yieldedthe desired product (114 mg, 82%), MS: m/e=352.3 (M+H⁺).

Example 4(10aS)-3-(9-Bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-ylmethyl)-oxazolidin-2-one

The title compound, MS: m/e=352.3 (M+H⁺) was prepared in accordance withthe general method of example 3 from(10aS)-9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole and2-oxazolidinone.

Example 5(10aR)-2-(9-Bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-ethanol

(10aR)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (0.10 g,0.39 mmol) and 2-(bromoethoxy)-tert-butyl-dimethylsilane (88 mg, 0.39mmol) were dissolved in acetonitrile (2 mL). Potassium carbonate (63 mg,0.46 mmol) was added and the solution was boiled with stirring for 2 d.The solvent was removed and the residue was partitioned betweendichloromethane and brine. The organic phases were pooled, dried withMgSO₄ and the solvent was evaporated. Chromatography on silica gel(dichloromethane/methanol 98:2) yielded the intermediate silyl-protectedalcohol (124 mg, 76%), MS: m/e=413.3 (M+H⁺).

The intermediate was dissolved in a mixture of ethanol (3 mL) andhydrochloric acid (conc. 0.1 mL) and stirred for 20 h at roomtemperature. Removal of the solvent was followed by partitioning betweenethylacetate and saturated sodium bicarbonate. Organic phases werepooled, dried with MgSO₄ and the solvent was evaporated. Chromatographyon silica gel (ethylacetate) yielded the desired product (50 mg, 58%),MS: m/e=297.2 (M+H⁺).

Example 6(10aR)-(9-Bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-aceticacid methyl ester

(10aR)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (0.07 g,0.27 mmol) and methyl bromoacetate (43 mg, 0.27 mmol) were dissolved inacetonitrile (2 mL). Potassium carbonate (44 mg, 0.32 mmol) was addedand the solution was boiled with stirring for 15 h. The solvent wasremoved and the residue was partitioned between dichloromethane andbrine. Organic phases were pooled, dried with MgSO₄ and the solvent wasevaporated. Chromatography on silica gel (dichloromethane/methanol 98:2)gave(10aR)-(9-bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-aceticacid methyl ester (57 mg, 63%), MS: m/e=325.2 (M+H⁺).

Example 7(10aR)-2-(9-Bromo-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl)-acetamide

The title compound, MS: m/e=310.1 (M+H⁺) was prepared in accordance withthe general method of example 6 from(10aR)-9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole and2-bromoacetamide.

Example 8(4R,10aR)-7-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

Compound 8 can be prepared as described in Example 9.

MS: m/e=222.1(M⁺), α_(D)²⁰ = −73.2

Example 9(4R,10aS)-7-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

(4R)-7-Chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (0.180g; 0.816 mmol) is dissolved in a tetrahydrofuran/trifluoroacetic acidmixture (1:2; 7.5 ml) and cooled to 0° C. Sodium borohydride (62 mg;1.63 mmol) was added and the solution was stirred for 2 h. The reactionmixture was poured in an aqueous NaOH solution, basified to ph 14 andextracted twice with ethyl-acetate. Organic phases were pooled, driedwith MgSO₄ and the solvent was evaporated. Chromatography on silica gel(dichloromethane/methanol 9:1) gave(4R,10aR)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(81 mg, 45%) and(4R,10aS)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(17 mg, 9%).

Example 10(4S,10aS)-7-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

Example 10 can be prepared as described in Example 11.

MS: m/e=222.1(M⁺), α_(D)²⁰ = +73.4

Example 11(4S,10aR)-7-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

(4S)-7-Chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (0.152g; 0.689 mmol) is dissolved in a tetrahydrofurane/trifluoroacetic acidmixture (1:2; 7.5 ml)and cooled to 0° C. Sodium borohydride (52 mg; 1.38mmol) is added and the solution was stirred for 2 h. The reactionmixture was poured in an aqueous NaOH solution (pH was put to 14) andextracted twice with ethyl-acetate. Organic phases were pooled, driedwith MgSO₄ and the solvent was evaporated. Chromatography on silica gel(dichloromethane/methanol 9:1) gave(4S,10aS)-7-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(113 mg, 74%) and(4S,10aR)-7-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(12 mg, 8%).

Intermediates(10aR)-9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole and(10aS)-9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

Sodiumhydride (4.0 g, 92 mmol) was suspended in dimethylformamide (20mL) and a solution of 4-bromo-1H-Indole-2-carboxylic acid ethyl ester(16.4 g, 61 mmol) in dimethylformamide (70 mL) was added. The mixturewas stirred for 1 h at room temperature and after cooling to 0° C.chloroacetonitrile (7.7 mL, 122 mmol) was added. After 1 h at roomtemperature the mixture was added to an ice/water mixture (800 mL) andextracted with ethylacetate. The organic phases were pooled washed withbrine, dried with MgSO₄ and the solvent was removed in vacuo.Chromatography on silica gel (ethyl acetate/n-hexane 4:1) yielded4-bromo-1-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (13.4 g,71%) as a colorless solid, MS: m/e=306.0 (M⁺).

Lithium aluminiumhydride (4.0 g, 106 mmol) was suspended in diethylether(600 mL) and 4-bromo-1-cyanomethyl-1H-indole-2-carboxylic acid ethylester (13.0 g, 42 mmol) was added in portions. The mixture was boiledfor 15 h, cooled to room temperature and added to saturated potassiumsodium tartrate solution. Thorough washing of the filter-cake with ethylacetate followed the filtration over Celite® to remove solids. Thephases of the filtrate were separated and the water phase was extractedwith ethylacetate. The organic phases were pooled, washed with brine,dried with MgSO₄ and the solvent was evaporated. Chromatography onsilica gel (dichloromethane/methanol 95:5) yielded9-bromo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (3.6 g, 34%) as acolorless solid, MS: m/e=250.0 (M⁺).

9-Bromo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (3.5 g, 13.9 mmol) wasdissolved in THF (15 mL) and trifluoroacetic acid (30 mL) and cooled to0° C. Sodium borohydride (1 g, 27.9 mmol) was added in portions, themixture was stirred for 90 min at room temperature and added to anice/water mixture (150 mL). After addition of sodium hydroxide solution(28%, 35 mL) to render the mixture basic it was extracted withdichloromethane. Organic phases were pooled, washed with brine, driedwith MgSO₄ and the solvent was evaporated. Chromatography on silica gel(dichloromethane/methanol/ammonia 180:10:1) yielded9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (2.4 g, 68%) as ayellowish solid, MS: m/e=252.0 (M⁺).

9-Bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (4.8 g, 18.8mmol) was dissolved in ethanol (42 mL) and separated into theenantiomers by chromatography on a preparative Chiralpak AD® column withheptane/ethanol (95:5) as eluent. This yielded after evaporation of thesolvent

-   (10aS)-9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (2.3    g, 48%) α_(D)²⁰ = −56.5-    and-   (10aR)-9-bromo-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole (2.2    g, 46%) α_(D)²⁰ = +49.0.

Intermediates(4R)-7-Chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2a]-indole and(4S)-7-chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2a]-indole

Sodiumhydride (0.89 g, 20.1 mmol) was suspended in dimethylformamide (15mL) and a solution of 6-chloro-11H-indole-2-carboxylic acid ethyl ester(2.00 g, 8.9 mmol) in dimethylformamide (8 mL) was added at 0° C. Themixture was stirred for 1 h at 0° C. then 2-bromo-propionitrile (3.6 g,23.95 mmol) was added. After 1 h at room temperature the mixture washeated at 75° C. for 18 hours. The reaction mixture was then added to anice/water mixture (1100 mL) and extracted with ethylacetate. The organicphases were pooled washed with brine, dried with Na₂SO₄ and the solventwas removed in vacuo. Chromatography on silica gel (ether/n-hexane 1:4)yielded 6-chloro-1-(cyano-methyl-methyl)-1H-indole-2-carboxylic acidethyl ester (2.06 g, 67%) as a colorless solid, MS: m/e=277.2 (M+H⁺).

6-Chloro-1-(cyano-methyl-methyl)-1H-indole-2-carboxylic acid ester ethyl(2.05 g; 7.4 mmol) was dissolved in tetrahydrofuran (25 mL). At 35° C.borane-dimethylsulfide complex (2M in THF; 11.1 ml; 22.2 mmol) was addedand the mixture was heated to reflux for 25 minutes, cooled to 0° C. andhydrochloric acid solution (25%; 3.5 ml; 27.7 mmol) was added carefully(strong hydrogen evolution). The mixture was heated at reflux for 30minutes then cooled to room temperature. The reaction mixture was thenadded to a chilled aqueous potassium carbonate solution (100 mL). Theorganic phases were extracted with ethylacetate.

The phases were separated and the water phase was extracted withethylacetate. Organic phases were pooled, washed with brine, dried withNa₂SO₄ and the solvent was evaporated.

The crude residue was dissolved in dry methanol (50 ml), potassiumcarbonate (2.05 g; 14.8 mmol) was added and the reaction mixture wasstirred at RT over night. The reaction mixture was then added to anice/water mixture (100 mL) and extracted with ethylacetate. The organicphases were pooled washed with brine, dried with Na₂SO₄ and the solventwas removed in vacuo. Chromatography on silica gel(dichloromethane/methanol 95:5) yielded7-chloro-4-methyl-3,4-dihydro-2H-pyrazino[1,2a]-indole-1-one (1.21 g,69%) as an off-white foam, MS: m/e=234.1 (M⁺).

7-Chloro-4-methyl-3,4-dihydro-2H-pyrazino[1,2a]-indole-1-one (1.02 g,4.34 mmol) was dissolved in THF (30 mL). Borane-dimethylsulfide complex(2M in THF; 20 ml; 40 mmol) was added and the mixture was heated toreflux for 3 hours. Then the reaction mixture was cooled to 0° C. and anaqueous hydrochloric acid solution (25%; 1.2 ml; 9.6 mmol) was addedcarefully (strong hydrogen evolution) The mixture was heated at refluxfor 30 minutes, cooled to room temperature then added to a chilledaqueous potassium carbonate solution (100 mL). The organic phases wereextracted with ethylacetate.

The phases were separated and the water phase was extracted withethylacetate. Organic phases were pooled, washed with brine, dried withNa₂SO₄ and the solvent was evaporated. Chromatography on silica gel(dichloromethane/methanol 95:5) yielded7-chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2a]-indole (0.626 g,65%) a yellow gum, MS: m/e=220.1 (M⁺).

7-chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2a]-indole (548 mg, 2.48mmol) was dissolved in ethanol (20 mL) and separated into theenantiomers by chromatography on a preparative Chiralpak AD® column withheptane/ethanol (9:1) as eluent. This yielded after evaporation of thesolvent

-   (4R)-7-chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2a]-indole (183    mg, 33%) and-   (4S)-7-chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2a]-indole (155    mg, 28%).

Example 12(4R,10aR)-4-Methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) (S)-5-Methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester:

To a solution of 11.15 g (S)-carbamic acid, (2-hydroxypropyl)-,1,1-dimethylethyl ester, in 100 mL tetrahydrofuran was added at −78° C.80 mL of a 1.6 M solution of n-butyllithium in n-hexane during 15 min.The resulting mixture was warmed to −15° C. and stirred for 45 min. Asolution of 7.5 g thionyl chloride in 50 mL tetrahydrofuran was addedduring 5 min. The mixture was then warmed to −15° C. and stirred for 90min. The reaction mixture was partitioned between ethyl acetate and 10%citric acid. The phases were separated and the organic phase was washedwith sodium bicarbonate and brine, dried over magnesium sulfate,evaporated and purified by chromatography on silica gel with 3:1hexane:ethyl acetate. The intermediate sulfamidite was taken up in 60 mLethyl acetate and 100 mL of a 10% solution of sodium metaperiodate wasadded. The mixture was cooled to 0° C. and 0.21 g ruthenium dioxidedihydrate was added and the mixture was stirred at this temperature for45 min. The phases were separated and the organic phase was purified bychromatography on silica gel with 2:1 hexane:ethyl acetate to yield 5.3g of the title compound as white crystals after recrystallization fromethanol (m.p.: 111.6-115° C.) α_(D)²⁰ = +37.1.b)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-2-carboxylicacid ethyl ester:

Sodium hydride (0.75 g, 17 mmol) was suspended in N,N-dimethylformamide(15 mL) and a solution of 6-trifluoromethyl-1H-indole-2-carboxylic acidethyl ester (3.6 g, 14 mmol) in N,N-dimethylformamide (15 mL) was addedwith cooling at 5° C. After 1 h(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester (4.0 g, 17 mmol) was added and the solution was allowedto reach room temperature over the weekend. The solution was partitionedbetween ice water (600 mL) and diethylether (2-×250 mL). The organiclayer was washed with ice water and brine, dried (MgSO₄), andevaporated. Chromatography on silica gel with n-hexane/diethylether(4:1) yielded the title product as yellow oil (5.1 g, 88%). ISP-MS:m/e=415.3 (M+H⁺), α_(D)²⁰ = −29.6c)(R)-4-Methyl-7-trifluoromethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one:

(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6-trifluoromethyl-1H-indole-2-carboxylicacid ethyl ester (4.9 g, 12 mmol) was dissolved in dichloromethane (40mL) and treated with trifluoroacetic acid (18.3 mL) at 0° C. Afterremoval of the ice bath, the solution was stirred for 30 min, andevaporated under reduced pressure. The residue was dissolved in methanol(40 mL), then after addition of saturated sodium bicarbonate solution(90 mL) the mixture was stirred for 20 h at room temperature. Water (100mL) was added and the mixture was extracted with dichloromethane (2×100mL). The organic layer was separated, washed with brine, dried (MgSO₄),and evaporated. Chromatography on silica gel with hexane/ethyl acetates(1:1) yielded the title compound as a white solid (2.9 g, 90%). M.p.:201-204° C., EI-MS: m/e=268.2 (M⁺), α_(D)²⁰ = +7.5d)(R)-4-Methyl-7-trifluoromethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

(R)-4-Methyl-7-trifluoromethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one(2.75 g; 10 mmol) was dissolved in diethylether (200 mL) and lithiumaluminium hydride (0.78 g, 21 mmol) was added in portions with cooling.The solution was stirred for 2 h at reflux temperature, cooled andhydrolyzed by sequential addition of water (3.0 mL), sodium hydroxidesolution (15%, 6.0 mL) and water (6.0 mL). Diethylether was added (100mL), the mixture was filtered and the filtrate evaporated. The residuewas stirred with hexane (20 mL) and diethylether (1 mL) to give thetitle compound as white solid (2.55 g, 97%).

M.p.: 123-125° C., ISP-MS: m/e=255.1 (M⁺), α_(D)²⁰ = −110.0e)(4R,10aR)-4-Methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

(R)-4-Methyl-7-trifluoromethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole(1.0 g; 4.0 mmol) was dissolved in a tetrahydrofurane/trifluoroaceticacid mixture (1:2; 15 mL) and cooled to 0° C. Sodium borohydride (300mg; 8.0 mmol) was added in portions and the solution was stirred for 2h. The reaction mixture was poured into ice water (60 mL) and the pH wasadjusted to 14 with concentrated NaOH solution. The mixture wasextracted with dichloromethane (3-×75 mL). Organic phases were pooled,dried with MgSO₄ and the solvent was evaporated. Chromatography onsilica gel (dichloromethane/methanol 9:1) gave the title compound (0.86g, 85%) as yellowish oil. The compound was precipitated as HCl salt fromdiethylether solution. White solid, m.p. 221-224° C.; ISP-MS: m/e=257.1(M+H⁺), α_(D)²⁰ = −48.1.

Example 13(4R,10aS)-4-Methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound was obtained as a side product in example 12 e) in6.3% yield (64 mg yellowish oil) and precipitated as HCl salt fromdiethylether. White solid, m.p. 245-250° C. dec.; ISP-MS: m/e=257.2(M+H⁺), α_(D)²⁰ = −101.6.

Example 14(4R,10aS)-6-Ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) 7-Ethyl-indole-1-carboxylic acid tert-butyl ester

7-Ethylindole (106.0 g, 0.73 mol) was dissolved in acetonitrile (11) anddi-tert-butyl dicarbonate (191.0 g, 0.87 mol) and4-(dimethylamino)pyridine (4.43 g, 36.0 mmol) were added successively.After 4.5 h the reaction mixture was concentrated and the residue waspurified by column chromatography over silica gel (0.032-0.060 mm) withn-hexane/tert-butyl methyl ether (9/1) as eluant to yield the desiredproduct as colorless oil (179 g, 100%). EI-MS: m/e=245.2 ([M])

b) 7-Ethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester

2,2,6,6-Tetramethylpiperidine (2.21 g, 15.6 mmol) was dissolved in 30 mLtetrahydrofuran and cooled down to −75° C. n-Butyllithium (9 mL, 14.3mmol, 1.6M solution in n-hexane) was added while maintaining thetemperature below −70° C. After 50 min., a solution of 3.2 g (13.0 mmol)7-ethyl-indole-1-carboxylic acid tert-butyl ester in 15 mLtetrahydrofuran was added and the temperature again kept below −70° C.After 50 min., ethyl chloroformate (1.4 mL (14.3 mmol) was added and thetemperature was allowed to rise to −50° C. After 1 h the reactionmixture was poured into 30 mL saturated aq. ammonium chloride solutionand the phases separated. The aqueous phase was extracted once with 50mL diethyl ether and the combined organic extractions were washedsuccessively with saturated aq. ammonium chloride solution and water,dried over magnesium sulfate, filtered and evaporated. The crudereaction product was flash-chromatographed over silica gel (0.030-0.060mm) with n-hexane/tert-butyl methyl ether (39/1) as eluant to give theproduct as a yellow oil (2.3 g, 56.2%). EI-MS: m/e=317.2 ([M])

c) 7-Ethyl-1H-indole-2-carboxylic acid ethyl ester

7-Ethyl-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester(76.6 g, 0.24 mol) was dissolved in 450 mL dichloromethane and cooled to0° C. Trifluoroacetic acid (150.0 mL, 1.96 mol) was added within 30 min.and after an additional 45 min. the reaction mixture was concentrated ata rotary evaporator. The residue was dissolved in 300 mL dichloromethaneand poured cautiously onto 500 mL saturated aq. sodium bicarbonatesolution. The phases were separated and the aqueous phase was extractedtwice with dichloromethane. The combined organic extracts were washedwith brine, dried over magnesium sulfate, filtered and concentrated on arotary evaporator. The residue was suspended in 400 mL n-hexane and putin an ultrasonic bath for 15 min. The suspension was filtered and thefilter cake was washed with 100 mL n-hexane. This procedure was repeatedto give the desired product as a light brown solid (40.2 g, 76.6%).EI-MS: m/e=217.1 ([M])

d) (R)-6-Ethyl-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

Potassium tert-butylate (2.17 g, 19.3 mmol) was added to a solution of7-ethyl-1H-indole-2-carboxylic acid ethyl ester (4.00 g, 18.4 mmol) inN,N-dimethylformamide (100 mL) at 0° C., then after 1 h(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester (4.81 g, 20.2 mmol) was added and the solution wasallowed to reach room temperature over 16 h. The solution waspartitioned between 1 M aq. HCl solution (100 mL) and hexane/ethylacetate 1:1 (200 mL). The organic layer was washed with sat. aq. NaHCO₃solution and brine, dried (MgSO₄), and evaporated. The residue wasdissolved in dichloromethane (80 mL) and treated with trifluoroaceticacid (20 mL) at 0° C. After removal of the ice bath, the solution wasstirred for 30 min, then evaporated under reduced pressure. The residuewas dissolved in methanol (100 mL), then after addition of K₂CO₃ (25.4g, 184 mmol) the mixture was stirred for 16 h at room temperature. Thenwater (200 mL) and ethyl acetate (200 mL) were added, the organic layerwas separated, washed with brine, dried (MgSO₄), and evaporated.Chromatography (70 g SiO₂, hexane/ethyl acetate gradient) yielded a foamwhich was precipitated with hexane to produce the title compound (1.20g, 29%). White solid. EI-MS: m/e=228.3 (M⁺). The optical purity wasdetermined by gas chromatography, using a chiral BGB-176-SE column (15m×0.25 mm), to be 96.2% e.e.

e)(4R,10aS)-6-Ethyl-4-methyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one.

Magnesium turnings (87 mg, 3.6 mmol) were added to a solution of(R)-6-Ethyl-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (82 mg,0.36 mmol) in methanol (4 mL). After hydrogen gas started to evolve, thereaction mixture was kept at 10-20° C. and stirred for 2 h to dissolvethe magnesium completely. Then the reaction mixture was poured onto 3 mLice-cold 1 M aq. HCl, neutralized with 1 M aq. potassium phosphatesolution (pH 6.85), and extracted with ethyl acetate. The organic layerwas washed with brine, dried (MgSO₄), and evaporated to yield the titlecompound (80 mg, 97%). White solid. ISP-MS: m/e=231.2 ([M+H]⁺).

f)(4R,10aS)-6-Ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

Lithium aluminium hydride (37 mg, 0.97 mmol) was added to a solution of(4R,10aS)-6-ethyl-4-methyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one(56 mg, 0.24 mmol) in tetrahydrofuran (3 mL) and the resultingsuspension was heated to reflux for 1 h. After cooling the reaction wasquenched by careful addition of 1 M aqueous sodium potassium tartratesolution (5 mL). Then methanol (5 mL) and ethyl acetate (5 mL) wereadded, the organic layer was separated, washed with brine, dried(MgSO₄), and evaporated. Chromatography on 20 g SiO₂ (CH₂Cl₂/MeOH/NH₄OH95:5:0.1) yielded the title compound (20 mg, 38%). White solid. ISP-MS:m/e=217.3 ([M+H]⁺).

Example 15(4R,10aR)-6-Ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (R)-6-Ethyl-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

Lithium aluminium hydride (532 mg) was added in portions to a solutionof (R)-6-ethyl-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (800mg, 3.50 mmol) in tetrahydrofuran (30 mL) and the resulting suspensionwas heated to reflux for 1 h. After cooling the reaction was quenched bycareful addition of 1 M aqueous sodium potassium tartrate solution (50mL). Then methanol (50 mL) and ethyl acetate (50 mL) were added, theorganic layer was separated, washed with brine, dried (MgSO₄), andevaporated to yield the title compound (750 mg, 100%). White solid.ISP-MS: m/e=215.3 ([M+H]⁺).

b)(4R,10aR)-6-Ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

This compound was prepared in accordance with the general method ofexample 12e) from(R)-6-ethyl-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole. Whitesolid. ISP-MS: m/e=217.4 ([M+H]⁺).

Example 16(4R,10aR)-8-Bromo-4-methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(4R,10aR)-4-Methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

(4R,10aR)-4-Methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(0.64 g, 2.5 mmol) were dissolved in dichloromethane (15 mL) anddi-tert-butyl dicarbonate (0.65 g, 3 mmol) dissolved in dichloromethane(2 mL) was added. The mixture was stirred for 1 h and solvent wasremoved in vacuo. Chromatography on silica gel (n-hexane/diethylether6:1) yielded the title product as a colorless oil (0.86 g, 96%).

ISP-MS: m/e=357.3 (M+H⁺).

b)(4R,10aR)-8-Bromo-4-methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

4-Methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (0.83 g; 2.4 mmol) was dissolved indimethylformamide (7 mL) and N-bromosuccinimide (0.43 g, 2.5 mmol) wasadded in portions. The mixture was stirred for 1 h, added to ice water(500 mL) and extracted with diethylether (2×150 mL). Organic phases werepooled, washed with water, dried with MgSO₄ and the solvent was removedin vacuo. Chromatography on silica gel (n-hexane/diethylether 4:1)yielded the title product as a colorless wax (0.99 g, 98%). ISP-MS:m/e=435.3, 437.3 (M+H⁺).

c)(4R,10aR)-8-Bromo-4-methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

8-Bromo-4-methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (0.35 g, 0.8 mmol) were dissolved indichloromethane (12 mL) and trifluoroacetic acid was added (3 mL). Themixture was stirred for 1 h, added to 1 N sodium hydroxide solution (50mL) and extracted with dichloromethane (3×40 mL). Organic phases werepooled, washed with brine, dried with MgSO₄ and the solvent was removedin vacuo. Chromatography on silica gel (dichloromethane/methanol 19:1)yielded the title compound as a colorless oil which was precipitated asHCl salt from diethylether (0.2 g; 73%). ISP-MS: m/e=335.2, 337.2(M+H⁺), α_(D)²⁰ = −48.6.

Example 17(4R,10aR)-4,6,7-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6,7-dimethyl-1H-indole-2-carboxylicacid ethyl ester

The title compound, ISP-MS: m/e=375.4 (M+H⁺), was prepared in accordancewith the general method of example 12b) from6,7-dimethyl-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

b) (R)-4,6,7-Trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, ISP-MS: m/e=229.2 (M+H⁺) and α_(D)²⁰ = −49.8,was prepared in accordance with the general method of example 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6,7-dimethyl-1H-indole-2-carboxylicacid ethyl ester.c) (R)-4,6,7-Trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound was prepared in accordance with the general method ofexample 12d) from(R)-4,6,7-trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

d)(4R,10aR)-4,6,7-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, ISP-MS: m/e=217.3 (M+H⁺) and α_(D)²⁰ = −8.1,was prepared in accordance with the general method of example 12e) from(R)-4,6,7-trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Example 18(4R,10aR)-7-Bromo-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride (1:1.25)

a)(R)-6-Bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-indole-2-carboxylicacid ethyl ester

The title compound, ISP-MS: m/e=425.3, 427.3 (M+H⁺), was prepared inaccordance with the general method of example 12b) from6-bromo-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

b) (R)-7-Bromo-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, ISP-MS: m/e=279.1, 281.1 (M+H⁺) and α_(D)²⁰ = −8.9,was prepared in accordance with the general method of example 12c) from(R)-6-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-indole-2-carboxylicacid ethyl ester.c) (R)-7-Bromo-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=265.2, 267.2 (M+H⁺) andα_(D)²⁰ = −115.7,was prepared in accordance with the general method of example 12d) from(R)-7-bromo-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.d)(4R,10aR)-7-Bromo-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, ISP-MS: m/e=267.2, 269.2 (M+H⁺) and α_(D)²⁰ = −44.9,was prepared in accordance with the general method of example 12e) from(R)-7-bromo-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Example 19(4R,10aR)-4,8-Dimethyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(4R,10aR)-4,8-Dimethyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

(4R,10aR)-8-Bromo-4-methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (0.38 g, 0.8 mmol) and methyl iodide (0.25 g, 1.6mmol) were dissolved in tert-butylmethylether (3 mL). A solution ofmethyl lithium in diethylether (0.66 mL, 1.6 M) was added with cooling(0° C.) and stirring. The mixture was stiired for ½ h at 0° C., water(25 mL) was added and the mixture was extracted with diethylether (2×20mL). Organic phases were pooled, dried with MgSO₄ and the solvent wasremoved in vacuo. Chromatography on silica gel (n-hexane/diethylether4:1) yielded the title product as light yellow oil (0.20 g, 63%).

b)(4R,10aR)-4,8-Dimethyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, ISP-MS: m/e=271.3 (M+H⁺) and α_(D)²⁰ = −43.3,was prepared in accordance with the general method of example 16c) from(4R,10aR)-4,8-dimethyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester.

Example 20(4R,10aR)-9-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-4-chloro-1H-indole-2-carboxylicacid ethyl ester

The title compound, m.p.: 115-119° C., ISP-MS: m/e=381.3 (M+H⁺) anda_(D) ²⁰=−8.0, was prepared in accordance with the general method ofexample 12b) from 4-chloro-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

b) (R)-9-Chloro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, m.p.: 180-184° C., EI-MS: m/e=234.1 (M⁺) andα_(D)²⁰ = +20.2,was prepared in accordance with the general method of example 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-4-chloro-1H-indole-2-carboxylicacid ethyl ester.c) (R)-9-Chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, ISP-MS: m/e=221.2 (M+H⁺) and α_(D)²⁰ = −110.6,was prepared in accordance with the general method of example 12d) from(R)-9-chloro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one andprecipitated as HCl salt from diethylether.d)(4R,10aR)-9-Chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, ISP-MS: m/e=223.2 (M+H⁺) and α_(D)²⁰ = −57.4,was prepared in accordance with the general method of example 12e) from(R)-9-chloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Example 21(4R,10aS)-4,8-Dimethyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) 5-Methyl-6-trifluoromethyl-indole-1-carboxylic acid tert-butyl ester

The title compound, EI-MS: m/e=299.1 (M⁺), was prepared in accordancewith the general method of example 14a) from5-methyl-6-trifluoromethyl-1H-indole

b) 5-Methyl-6-trifluoromethyl-indole-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester

The title compound, EI-MS: m/e=371.1 (M⁺), was prepared in accordancewith the general method of example 14b) from5-methyl-6-trifluoromethyl-indole-1-carboxylic acid tert-butyl ester

c) 5-Methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester

The title compound, m.p.: 176-178° C. and EI-MS: m/e=271.1 (M⁺), wasprepared in accordance with the general method of example 14c) from5-methyl-6-trifluoromethyl-indole-1,2-dicarboxylic acid 1-tert-butylester 2-ethyl ester

d)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-5-methyl-6-trifluoromethyl-1H-indole-2-carboxylicacid ethyl ester

The title compound, m.p.: 103-105° C., EI-MS: m/e=428.1(M⁺) andα_(D)²⁰ = −40.3,was prepared in accordance with the general method of example 12b) from5-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.e)(R)-4,8-Dimethyl-7-trifluoromethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, ISP-MS: m/e=283.1 (M+H⁺) and α_(D)²⁰ = +4.3,was prepared in accordance with the general method of example 12c) from(R)-1-(2-tert-butoxycarbonylamino1-methyl-ethyl)-5-methyl-6-trifluoromethyl-1H-indole-2-carboxylic acidethyl ester.f)(4R,10aS)-4,8-Dimethyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

m.p.: 200-205° C., ISP-MS: m/e=271.3 (M+H⁺) and α_(D)²⁰ = −103.1,(R)-4,8-Dimethyl-7-trifluoromethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

Example 22(4R,10aR)-7-Chloro-8-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylicacid ethyl ester

The title compound, ISP-MS: m/e=399.4 (M+H⁺), was prepared in accordancewith the general method of example 12b) from6-chloro-5-fluoro-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

b)(R)-7-Chloro-8-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, ISP-MS: m/e=253.1 (M+H⁺) and α_(D)²⁰ = −6.7,was prepared in accordance with the general method of example 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6-chloro-5-fluoro-1H-indole-2-carboxylicacid ethyl ester.c)(R)-7-Chloro-8-fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=239.2 (M+H⁺) and α_(D)²⁰ = −121.7,was prepared in accordance with the general method of example 12d) from(R)-7-chloro-8-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.d)(4R,10aR)-7-Chloro-8-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride.

The title compound, ISP-MS: m/e=241.3 (M+H⁺) and α_(D)²⁰ = −48.2,was prepared in accordance with the general method of example 12e) from(R)-7-chloro-8-fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Example 23(4R,10aS)-8-Bromo-4-methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(4R,10aS)-4-Methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

The title compound, ISP-MS: m/e=357.3 (M+H⁺), was prepared in accordancewith the general method of example 16a) from(4R,10aS)-4-methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole.

b)(4R,10aS)-8-Bromo-4-methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

The title compound, ISP-MS: m/e=435.3, 437.3 (M+H⁺), was prepared inaccordance with the general method of example 16b)from(4R,10aS)-4-methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester.

c)(4R,10aS)-8-Bromo-4-methyl-7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, ISP-MS: m/e=335.1, 337.1 (M+H⁺) and α_(D)²⁰ = −79.1,was prepared in accordance with the general method of example 16c)from(4R,10aS)-8-Bromo-4-methyl-7-trifluoromethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester.

Example 24(4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-7-carbonitrilehydrochloric acid

a)(4R,10aR)-7-Bromo-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

The title compound, ISP-MS: m/e=367.1, 369.1 (M+H⁺) and α_(D)²⁰ = −36.9,was prepared in accordance with the general method of example 16a) from(4R,10aR)-7-bromo-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole.b)(4R,10aR)-7-Cyano-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

(4R,10aR)-7-Bromo-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (0.1 g) was dissolved in dioxane (2 mL) andcopper(I)cyanide (0.1 g), tris-(dibenzylideneacetone)dipalladiumchloroform complex (12 mg), 1,1′-bis(diphenylphosphino)ferrocene (24 mg)and tetraethylammonium cyanide (43 mg) were added. The mixture washeated to reflux for 18 h, cooled, filtered and the filter cake waswashed with ethyl acetate. Saturated sodium bicarbonate solution (30 mL)was added to the filtrate, the phases were separated, the water phasewas extracted with ethyl acetate (2-×20 mL) and the organic phaseswashed twice with saturated bicarbonate solution. Organic phases werepooled, dried with MgSO₄ and the solvent removed in vacuo.Chromatography on silica gel (n-hexane/ethyl acetate 6:1) yielded thetitle compound as light yellow wax (34 mg; 40%). ISP-MS: m/e=314.2(M+H⁺).

c)(4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-7-carbonitrilehydrochloric acid:

The title compound, ISP-MS: m/e=214.3 (M+H⁺), was prepared in accordancewith the general method of example 16c) from(4R,10aR)-7-cyano-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester.

Example 25(4R,10aR)-9-Chloro-6-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) (5-Chloro-2-fluoro-phenyl)-hydrazine

5-Chloro-2-fluoroaniline (25 g, 172 mmol) was added to conc.hydrochloric acid (150 mL, 37%). The mixture was cooled (−10° C.) and asolution of sodium nitrite (11.9 g, 172 mmol) in water (193 mL) wasadded slowly (<-5° C.). This done, a solution of tin(II)chloride (118 g,618 mmol) in conc. hydrochloric acid (116 mL) was added slowly (−6° C.).The mixture was stirred for 1 h, filtered through Celite® and the filtercake washed extensively with water. The filtrate was adjusted to pH 14with conc. sodium hydroxide solution and the suspension extracted withdiethylether. Organic phases were pooled, washed with brine, dried withMgSO₄ and the solvent was removed in vacuo to yield the title compoundas yellow solid (22.9 g, 83%), EI-MS: m/e=160.0 (M⁺).

b) 2-[(5-Chloro-2-fluoro-phenyl)-hydrazono]-propionic acid ethyl ester

(5-Chloro-2-fluoro-phenyl)-hydrazine (22.5 g, 140 mmol) was dissolved indichloromethane (80 mL). Ethyl pyruvate (16.3 mL, 140 mmol) was addedslowly to this solution at room temperature. The mixture was stirred foranother 1 h at room temperature, added to water and extraxcted withdichloromethane. Organic phases were pooled, washed subsequently withhydrochloric acid (1 N) and brine and dried with MgSO₄. Solvents wereremoved in vacuo and the residue was triturated with n-hexane to yieldthe title product as beige solid (22.8 g, 62.9%), ISP-MS: m/e=259.1(M+H⁺).

c) 4-Chloro-7-fluoro-1H-indole-2-carboxylic acid ethyl ester

2-[(5-Chloro-2-fluoro-phenyl)-hydrazono]-propionic acid ethyl ester(13.2 g, 51 mmol) was dissolved in toluene, p-toluenesulfonic acid (10g, 51 mmol) was added and the mixture was heated to reflux for 24 h withseparation of water. The mixture was cooled, neutralized with saturatedsodium bicarbonate (400 mL) and extracted thrice with ethyl acetate.Organic phases were pooled, washed with brine, dried with MgSO₄ and thesolvent was removed in vacuo. The residue was triturated with hexane toyield the title product as yellowish solid (2.9 g, 23%); EI-MS:m/e=241.1 (M⁺).

d)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-4-chloro-7-fluoro-1H-indole-2-carboxylicacid ethyl ester

The title compound, ISP-MS: m/e=399.4 (M+H⁺) and α_(D)²⁰ = −54.7,was prepared in accordance with the general method of example 12b) from4-chloro-7-fluoro-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.e)(R)-9-Chloro-6-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, ISP-MS: m/e=253.1 (M+H⁺) and α_(D)²⁰ = +22.7,was prepared in accordance with the general method of example 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-4-chloro-7-fluoro-1H-indole-2-carboxylicacid ethyl ester.f)(4R,10aR)-9-Chloro-6-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

(R)-9-Chloro-6-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one(1.2 g, 4.7 mmol) was dissolved in methanol and magnesium (0.69 g, 28.5mmol) was added with stirring. Stirring was continued for 3 h at roomtemperature, the mixture was poured onto ice water and hydrochloric acid(1 N, 23 mL) was added. The pH was adjusted to neutral with potassiumphosphate buffer (1 M, pH 6.85) and the mixture was extracted with ethylacetate. Organic phase were pooled, washed with brine, dried with MgSO₄and the solvent was removed in vacuo to yield a mixture of (4R,10aR)-and(4R,10aS)-9-chloro-6-fluoro-4-methyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one.Without further purification this mixture (1.2 g) was dissolved indiethylether (50 mL), lithium aluminium hydride (460 mg, 12.0 mmol) wasadded and the mixture was heated to reflux for 4 h. The solution wascooled and hydrolyzed by sequential addition of water (6.0 mL), sodiumhydroxide solution (15%, 12.0 mL) and water (12.0 mL). Diethylether wasadded (300 mL), the mixture was filtered and the filtrate was evaporatedafter drying with MgSO₄. Chromatography on silica gel(dichloromethane/methanol 97:3) separated the title compound (0.23 g;20%) from the isomeric(4R,10aS)-9-chloro-6-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole.The title compound was characterized as its HCl salt which precipitatedfrom diethylether, ISP-MS: m/e=241.3 (M+H⁺) and α_(D)²⁰ = −18.4.

Example 26(4R,10aR)-6,7-Difluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) 2-[(2,3-Difluoro-phenyl)-hydrazono]-propionic acid ethyl ester

The title compound, EI-MS: m/e=242.1 (M+), was prepared in accordancewith the general method of example 25b) from 2,3-difluorophenylhydrazine and ethyl pyruvate.

b) 6,7-Difluoro-1H-indole-2-carboxylic acid ethyl ester

The title compound, EI-MS: m/e=225.1 (M⁺), was prepared in accordancewith the general method of example 25c) from2-[(2,3-difluoro-phenyl)-hydrazono]-propionic acid ethyl ester.

c)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6,7-difluoro-1H-indole-2-carboxylicacid ethyl ester

The title compound, ISP-MS: m/e=383.3 (M+H⁺), was prepared in accordancewith the general method of example 12b) from6,7-difluoro-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

d) (R)-6,7-Difluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, EI-MS: m/e=236.1 (M⁺), was prepared in accordancewith the general method of example 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6,7-difluoro-1H-indole-2-carboxylicacid ethyl ester.

e)(4R,10aR)-6,7-Difluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, EI-MS: m/e=224.2 (M+) and α_(D)²⁰ = −27.3,was prepared in accordance with the general method of example 25f) from(R)-6,7-difluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one andseparated from its (4R,10aS)-isomer by chromatography on silica gel.

Example 27(4R,10aS)-6,7-Difluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, EI-MS: m/e=224.2 (M⁺) and α_(D)²⁰ = −37.8,was prepared in accordance with the general method of example 25f) from(R)-6,7-difluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one andseparated from its (4R,10aR)-isomer by chromatography on silica gel.

Example 28(4R,10aR)-7-Chloro-6-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) (3-Chloro-2-fluoro-phenyl)-hydrazine

The title compound, EI-MS: m/e=200.0 (M⁺), was prepared in accordancewith the general method of example 25a) from 3-chloro-2-fluoroaniline.

b) 2-[(3-Chloro-2-fluoro-phenyl)-hydrazono]-propionic acid ethyl ester

The title compound, EI-MS: m/e=258.1 (M⁺), was prepared in accordancewith the general method of example 25b) from(3-Chloro-2-fluoro-phenyl)-hydrazine and ethyl pyruvate.

c) 6-Chloro-7-fluoro-1H-indole-2-carboxylic acid ethyl ester

The title compound, EI-MS: m/e=241.0 (M⁺), was prepared in accordancewith the general method of example 25c) from2-[(3-chloro-2-fluoro-phenyl)-hydrazono]-propionic acid ethyl ester.

d)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6-chloro-7-fluoro-1H-indole-2-carboxylicacid ethyl ester

The title compound, ISP-MS: m/e=399.4 (M+H⁺), was prepared in accordancewith the general method of example 12b) from6-chloro-7-fluoro-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

e)(R)-7-Chloro-6-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, EI-MS: m/e=252.1 (M⁺), was prepared in accordancewith the general method of example 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6-chloro-7-fluoro-1H-indole-2-carboxylicacid ethyl ester.

f)(4R,10aR)-7-Chloro-6-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, ISP-MS: m/e=241.3 (M+H⁺) and α_(D)²⁰ = −39.1,was prepared in accordance with the general method of example 25f) from(R)-7-chloro-6-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-oneand separated from its (4R,10aS)-isomer by chromatography on silica gel.

Example 29(4RS,10aRS)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (RS)-5-ethyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester

The title compound was prepared in accordance to the general method ofexample 12a) from (RS)-(2-hydroxybutyl)-carbamic acid tert-butyl ester.White solid, m.p. 116-118° C. (dec.).

b) (RS)-7-Bromo-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound (ISP-MS: m/e=293.2, 295.2 ([M+H]⁺)) was produced inaccordance with the general method of example 14d) from6-bromo-1H-indole-2-carboxylic acid ethyl ester and(RS)-5-ethyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester. White solid.

c) (RS)-7-Bromo-4-ethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=279.1, 281.2 ([M+H]⁺), was produced inaccordance with the general method of example 12d) from(RS)-7-bromo-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.Colorless oil.

d)(4RS,10aRS)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, m/e=281.1, 283.1 ([M+H]⁺), was produced from(RS)-7-bromo-4-ethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole inaccordance with the general method of example 12e) and separated fromthe isomeric(4RS,10aSR)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,by chromatography on silica gel. Colorless oil.

Example 30(4RS,10aSR)-7-Bromo-4-ethyl-1,2,3,4,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, m/e=281.1, 283.1 ([M+H]⁺), was produced as describedin example 29d). Colorless gum.

Example 31(4RS,10aRS)-6,7,8-Tribromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

Bromine (0.2 M solution, in acetic acid, 0.36 mL, 72 μmol) was addeddropwise to a solution of(4RS,10aRS)-7-bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(20 mg, 71 μmol) and sodium acetate (5.8 mg, 72 μmol) in acetic acid(0.5 mL) at room temperature. After 5 min the reaction mixture wasdiluted with ethyl acetate, washed with 1 M aq. sodium hydroxidesolution and brine, dried (MgSO₄), and evaporated. Chromatography onSiO₂ (CH₂Cl₂/MeOH/NH₄OH 95:5:0.25) yielded the title compound (16 mg,50%). Colorless gum, m/e=437.1, 439.1, 441.1, 443.1 ([M+H]⁺).

Example 32(4RS,10aRS)-7,8-Dibromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(4RS,10aRS)-7-Bromo-4-ethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

The title compound, m/e=380.1, 382.1 (M⁺), was produced in accordancewith the general method of example 16a) from(4RS,10aRS)-7-bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole.Colorless waxy solid.

b)(4RS,10aRS)-7,8-Dibromo-4-ethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

The title compound, m/e=459.2, 461.2, 463.2 ([M+H]⁺), was produced inaccordance with the general method of example 16b) from(4RS,10aRS)-7-bromo-4-ethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester. Colorless gum.

c)(4RS,10aRS-7,8-Dibromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, m/e=359.0, 361.0, 363.0 ([M+H]⁺), was produced inaccordance with the general method of example 16c) from(4RS,10aRS)-7,8-Dibromo-4-ethyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester. Colorless gum.

Examples 33 and 34(4R,10aR)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoleand(4S,10aS)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

(4R,10aR)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(100 mg, 0.36 mmol) was subjected to chromatographic separation using aChiralcel® OD-H column and heptane/2-propanol 95:5 as the eluant. Thisyielded(4R,10aR)-7-bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(35 mg, 35%; colorless oil; m/e 281.1, 283.1 ([M+H]⁺);α_(D)²⁰: − 16.5, α₃₆₅²⁰: + 92,and its enantiomer,(4S,10aS)-7-Bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(30 mg, 30%, colorless oil, m/e=281.1, 283.1 ([M+H]⁺);α_(D)²⁰: + 19.9, α₃₆₅²⁰: − 92).

Example 35(4RS,10aSR)-4-Ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, m/e=202.2 (M⁺), was produced in accordance with thegeneral method of example 25f) from(RS)-7-bromo-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one andseparated from the isomeric(4RS,10aRS)-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole bychromatography on silica gel. Colorless gum.

Example 36(4RS,10aRS)-4-Ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, m/e=202.2 (M⁺), was produced as described in example35. Colorless gum.

Example 37(4R,10aR)-8-Bromo-6-ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

Bromine (0.2 M solution in acetic acid, 0.48 mL, 96 μmol) was addeddropwise at room temperature to a solution of(4R,10aR)-6-ethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole(21 mg, 97 μmol) and sodium acetate (8.0 mg, 97 μmol) in acetic acid(0.5 mL). After 30 min the reaction mixture was diluted withdichloromethane and extracted with 2 M aq. potassium hydroxide solution,dried (MgSO₄), and evaporated. Chromatography on SiO₂ (CH₂Cl₂/MeOH/NH₄OH95:5:0.1) yielded the title compound (9 mg, 31%). Yellow oil. ISP-MS:m/e=295.3, 297.3 ([M+H]⁺).

Example 38(4R,10S,10aR)-4,6,10-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (R)-4,6,10-Trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, m/e=229.2 ([M+H]⁺), was produced in accordance withthe general method of example 14d) from3,7-dimethyl-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester. White solid.

b) (R)-4,6,10-Trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole oxalate

(R)-4,6,10-Trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (200 mg,0.88 mmol) was reacted with lithium aluminum hydride in accordance withthe general method of example 15a). The crude material obtained wasdissolved in ether (10 mL) and treated with oxalic acid solution (20% inethanol, 7 mL). The precipitate was collected by filtration and dried toafford the title compound (196 mg, 74%). White solid. Anal. calc. forC₁₆H₂₀N₂O₄: C, 63.14; H, 6.62; N, 9.20; found: C, 62.86; H, 6.87; N,8.92.

c)(4R,10S,10aR)-4,6,10-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, m/e=216.2 (M⁺), was produced in accordance with thegeneral method of example 12e) from(R)-4,6,10-trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole oxalateand separated from the isomeric(4R,10R,10aR)-4,6,10-trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoleby chromatography on silica gel. Colorless oil.

Example 39(4R,10R,10aR)-4,6,10-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, m/e=216.2 (M⁺), was produced as described in example38c). Colorless oil.

Examples 40 and 41(4R,10aR)-8-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and(4R,10aS)-8-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) (Z)-2-Azido-3-(3-fluoro-4-methyl-phenyl)-acrylic acid ethyl ester

To ethanol (200 ml) was added portionwise 6.7 g sodium metal in such away that the temperature stayed below 50° C. After all sodium haddissolved, the temperature was brought to −5° C. and a solution of3-fluoro-4-methylbenzaldehyde (10.0 g, 0.072 mol) and azido acetic acidethyl ester (37.4 g, 0.29 mol) in 100 ml ethanol was added whilemaintaining the temperature below 5° C. After 3 h the orange-redsolution was poured on saturated aqueous ammonium chloride solution andethyl acetate (300 ml) and water (100 ml) was added. The phases wereseparated, the aqueous phase was reextracted three times with ethylacetate (300 ml each) and the combined organic layers were washed withbrine (400 ml) and dried over magnesium sulfate. The crude reactionproduct was purified by column chromatography over silical gel(0.030-0.063 mm) with n-hexane/tert-butyl methyl ether (50/1) as eluentto yield the title product as a yellow oil (9.8 g, 54.2%). EI-MS:m/e=249.1 (M)

b) 5-Fluoro-6-methyl-1H-indole-2-carboxylic acid ethyl ester

(Z)-2-Azido-3-(3-fluoro-4-methyl-phenyl)-acrylic acid ethyl ester (9.7g, 0.039 mol) was dissolved in 80 ml p-xylene and divided into fourportions which were refluxed for 1 h. The oil bath was removed and theyellow solutions were cooled to 15° C. The resulting suspensions werefiltered, washed with n-hexane and the solid material collected. Thecombined mother liquors were evaporated and the resulting oil waspurified on silical gel (0.030-0.063 mm) with n-hexane/tert-butyl methylether (50/1) as eluent. The purified fractions together with the firstprecipitates were combined and chromatographed again to yield thedesired product as a colorless solid (3.2 g, 37.2%). EI-MS: m/e=249.1(M).

c)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-5-fluoro-6-methyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 5-fluoro-6-methyl-1H-indole-2-carboxylic acid ethylester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester.

Leight beige solid. ISP-MS: m/e=379.4 (M+H⁺).

d) (R)-8-Fluoro-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-5-fluoro-6-methyl-1H-indole-2-carboxylicacid ethyl ester.

Colorless solid. EI-MS: m/e=232.1 (M).

(e)4R,10aR)-8-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

and

(4R,10aS)-8-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compounds were produced in accordance with the general methodof example 25f) from(R)-8-fluoro-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

(4R,10aR) Isomer: Light brown solid. EI-MS: m/e=220.2 (M).

(4R,10aS) Isomer: Light brown solid. EI-MS: m/e=220.2 (M).

Examples 42 and 43(4R,10aR)-6-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;hydrochloride and(4R,10aS)-6-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;hydrochloride

a) 7-Fluoro-6-methyl-1H-indole-2-carboxylic acid ethyl ester

This compound (2.4 g, 27.9%) was obtained in accordance to step b,Examples 41 and 42. Colorless solid. EI-MS: m/e=249.1 (M).

b)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-7-fluoro-6-methyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 7-fluoro-6-methyl-1H-indole-2-carboxylic acid ethylester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester.

Leight beige solid. ISP-MS: m/e=379.4 (M+H⁺).

c) (R)-6-Fluoro-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-7-fluoro-6-methyl-1H-indole-2-carboxylicacid ethyl ester.

Colorless solid. EI-MS: 232.1 (M).

d)(4R,10aR)-6-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and

(4R,10aS)-6-Fluoro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride.

The title compounds were produced in accordance with the general methodof example 25f) from(R)-6-fluoro-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

(4R,10aR) Isomer: Off-white solid. EI-MS: m/e=220.2 (M).

(4R,10aS) Isomer: Light brown solid. EI-MS: m/e=220.2 (M).

Example 44(4R,10aR)-8-Fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-5-fluoro-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 5-fluoro-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

Colorless solid. ISP-MS: m/e=387.3 (M+Na⁺).

b) (R)-8-Fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-5-fluoro-1H-indole-2-carboxylicacid ethyl ester.

Colorless solid. ISP-MS: m/e=219.2 (M+H⁺).

c) (R)-8-Fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound was prepared in accordance with the general method ofexample 12d) from(R)-8-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

Yellow oil. ISP-MS: m/e=205.2 (M+H⁺).

d)(4R,10aR)-8-Fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound was prepared in accordance with the general method ofexample 12e) from(R)-8-fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Brown solid. ISP-MS: m/e=207.2 (M+H⁺).

Examples 45 and 46(4R,10aR)-4,6-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and(4R,10aS)-4,6-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-7-methyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 7-methyl-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

Colorless solid. ISP-MS: m/e=383.3 (M+Na⁺).

b) (R)-4,6-Dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-7-methyl-1H-indole-2-carboxylicacid ethyl ester.

Colorless powder. ISP-MS: m/e=215.3 (M+H⁺).

c) (4R,10aR)-4,6-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and(4R,10aS)-4,6-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compounds were produced in accordance with the general methodof example 25f) from(R)-4,6-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

(4R,10aR) Isomer: Light brown solid. ISP-MS: m/e=203.2 (M+H⁺).

(4R,10aS) Isomer: Brown solid. ISP-MS: m/e=203.3 (M+H⁺).

Example 47(4R,10aR)-7-Bromo-9-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) 6-Bromo-4-fluoro-1H-indole-2-carboxylic acid ethyl ester

The title compound was produced in accordance with the general method ofexamples 40 and 41, steps a and b), starting from4-bromo-2-fluorobenzaldehyde and azido acetic acid ethyl ester.Colorless powder.

¹H-NMR (CDCl₃): δ [ppm]=1.35 (t, 3H), 4.36 (q, 2H), 7.15 (d, 1H), 7.17(s, 1H), 7.47 (s, 1H), 12.4 (s, br, 1H).

b)(R)-6-Bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-4-fluoro-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 6-bromo-4-fluoro-1H-indole-2-carboxylic acid ethylester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester.

Colorless solid. ISP-MS: m/e=465.0 and 467.2 (M+Na⁺).

c)(R)-7-Bromo-9-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-6-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-4-fluoro-1H-indole-2-carboxylicacid ethyl ester.

Colorless powder. ISP-MS: m/e=297.2 and 299.0 (M+H⁺).

c)(R)-7-Bromo-9-fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound was produced in accordance with the general method ofexample 12d) from(R)-7-bromo-9-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

Colorless solid. ISP-MS: m/e=283.0 and 285.0 (M+H⁺).

c)(4R,10aR)-7-Bromo-9-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound was prepared in accordance with the general method ofexample 12e)from(R)-7-bromo-9-fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Light brown solid. ISP-MS: m/e=285.0 and 287.1 (M+H⁺).

Example 48(4R,10aR)-6-Fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-7-fluoro-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 7-fluoro-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

Colorless powder. ISP-MS: m/e=387.3 (M+Na⁺).

b) (R)-6-Fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-7-fluoro-1H-indole-2-carboxylicacid ethyl ester.

Colorless crystals. ISP-MS: m/e=219.2 (M+H⁺).

c) (R)-6-Fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound was produced in accordance with the general method ofexample 12d) from(R)-6-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

Yellow oil. ISP-MS: m/e=205.2 (M+H⁺).

d)(4R,10aR)-6-Fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound was prepared in accordance with the general method ofexample 12e) from(R)-6-fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Light brown solid. ISP-MS: m/e=207.2 (M+H⁺).

Example 49

(4R,10aR)-6,9-Difluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;hydrochloride

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-4,7-difluoro-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 4,7-difluoro-1H-indole-2-carboxylic acid ethyl esterand (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

Colorless crystals. ISP-MS: m/e=383.3 (M+H⁺).

b) (R)-6,9-Difluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-4,7-difluoro-1H-indole-2-carboxylicacid ethyl ester.

Colorless powder. ISP-MS: m/e=237.1 (M+H⁺).

c)(4R,10aR)-6,9-Difluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound was produced in accordance with the general method ofexample 25f)from(R)-6,9-difluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

Light brown solid. ISP-MS: m/e=225.2 (M+H⁺).

Examples 50 and 51(4R,10aR)-7,9-Dichloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and(4R,10aS)-7,9-Dichloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-4,6-dichloro-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 4,6-dichloro-1H-indole-2-carboxylic acid ethyl esterand (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

Yellow solid. ISP-MS: m/e=415.3 (M+H⁺).

b) (R)-7,9-Dichloro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-4,6-dichloro-1H-indole-2-carboxylicacid ethyl ester.

Colorless powder. ISP-MS: m/e=269.2 (M+H⁺).

c)(4R,10aR)-7,9-Dichloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and

(4R,10aS)-7,9-Dichloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride.

The title compounds were produced in accordance with the general methodof example 25f) from(R)-7,9-dichloro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

(4R,10aR) Isomer: Light yellow solid. ISP-MS: m/e=257.1 (M+H⁺).

(4R,10aS) Isomer: Light brown solid. ISP-MS: m/e=257.1 (M+H⁺).

Example 52(4R,10aR)-4,7,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-4,6-dimethyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 4,6-dimethyl-1H-indole-2-carboxylic acid ethyl esterand (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

Brown solid. ISP-MS: m/e=375.4 (M+H⁺).

b) (R)-4,7,9-Trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-4,6-dimethyl-1H-indole-2-carboxylicacid ethyl ester.

Colorless powder. EI-MS: m/e=228.3 (M).

c)(4R,10aR)-4,7,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound was produced in accordance with the general method ofexample 25f) from(R)-4,7,9-trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

Brown solid. ISP-MS: m/e=217.3 (M+H⁺).

Example 53(4R,10aS)-6-Bromo-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(R)-7-Bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-indole-2-carboxylicacid ethyl ester

The title compound was produced in accordance with the general method ofexample 12b) from 7-bromo-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

Yellow oil. ISP-MS: m/e=425.3 and 427.3 (M+H⁺).

b) (R)-6-Bromo-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was produced in accordance with the general method ofexample 12c) from(R)-7-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1H-indole-2-carboxylicacid ethyl ester.

Colorless crystals. ISP-MS: m/e=279.1 and 281.1 (M+H⁺).

c) (R)-6-Bromo-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indolehydrochloride

The title compound was produced in accordance with the general method ofexample 12d)from(R)-6-bromo-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

Beige powder. EI-MS: m/e=264.1 and 266.1 (M).

d)(4R,10aS)-6-Bromo-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound was produced in accordance with the general method ofexample 12e) from(R)-6-bromo-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indolehydrochloride.

Light brown solid. ISP-MS: m/e=267.2 and 269.2 (M+H⁺).

Example 54(4R,10aR)-7-Fluoro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound was prepared in accordance with the general method ofexample 12e) from(R)-7-fluoro-4,6-dimethyl-1,2,3,4-tetrahydro-2H-pyrazino[1,2-a]indole.Off-white solid, ISP MS: 221.3 (M+H)⁺

a) 6-Fluoro-7-methyl-1H-indole-2-carboxylic acid ethyl ester

3-Fluoro-2-methyl-phenylhydrazine (8.4 g, 0.06 mol) was dissolved inethanol and the solution cooled to 0° C. (ice-bath). ethyl pyruvate (6.9ml, 0.062 mol) was added dropwise and the solution stirred 15 h at roomtemperature. The solvent was evaporated under reduced pressure, and theresidue stirred with hexane. The mixture of hydrazones that formed uponcooling in an ice-bath was filtered and dried under vacuum. Yield: 9.1g, 64%. The hydrazone mixture (7.6 g, 0.032 mol) was dissolved intoluene (45 ml), anhydrous p-toluenesulfonic acid (8.2 g, 0.048 mol)added and the mixture heated 1 h at reflux. The mixture was cooled toroom temperature, poured into half-saturated aqueous sodium hydrogencarbonate and extracted twice with ethyl acetate. The combined organicphases were washed with brine, dried over magnesium sulfate andevaporated. The residue was purified by column chromatography on silicagel (8:1 to 6:1 hexane/ethyl acetate eluant) to afford the product as alight brown solid (1.68 g, 24%). EI MS: 221.1 (M⁺)

b)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6-fluoro-7-methyl-1H-indole-2-carboxylicacid ethyl ester

The title compound, ISP-MS: m/e=(M+H⁺), was prepared in accordance withthe general method of example 12b) from6-fluoro7-methyl-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester. Yellow solid, ISP MS: 379.4 (M+H)⁺

c) (R)-7-Fluoro-4,6-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

The title compound was prepared in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6-fluoro-7-methyl-1H-indole-2-carboxylicacid ethyl ester. White solid, ISP-MS: 233.1 (M+H)⁺

d) (R)-7-Fluoro-4,6-dimethyl-1,2,3,4-tetrahydro-2H-pyrazino[1,2-a]indole

The title compound was prepared in accordance with the general method ofexample 12d) from(R)-7-fluoro-4,6-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.Off-white solid, EI-MS: 218.1 (M⁺)

Example 55(4R,10aS)-7-Chloro-4,8-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=237.2 ([M+H]⁺), was produced inaccordance with the general method of example 12e) from(R)-7-Chloro-4,8-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole (seeExample 56).

Example 56(4R,10aR)-7-Chloro-4,8-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=237.2 ([M+H]⁺), was produced inaccordance with the general method of example 12e) from(R)-7-Chloro-4,8-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

a) (R)-7-Chloro-4,8-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

The title compound, ISP-MS: m/e=235.2 ([M+H]⁺), was produced inaccordance with the general method of example 12d) from(R)-7-chloro-4,8-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.Yellow foam.

b) (R)-7-Chloro-4,8-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

The title compound (ISP-MS: m/e=249.2 (M⁺+H)) was produced in accordancewith the general method of example 14d) from6-chloro-5-methyl-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester. Yield: 34%. Yellow solid.

Example 57(4R,10aR)-4-Methyl-6-trifluoromethoxy-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=273.2 ([M+H]⁺), was produced inaccordance with the general method of example 12e) from(R)-4-methyl-6-trifluoromethoxy-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

a)(R)-4-Methyl-6-trifluoromethoxy-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound was produced in accordance with the general method ofexample 12d) from(R)-4-methyl-6-trifluoromethoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one(light yellow solid, Mp: 58-60° C.; EI-MS: m/e=270.1 (M⁺).

b)(R)-4-Methyl-6-trifluoromethoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

Sodium hydride (280 mg of a 60% dispersion in mineral oil, 7 mmol) wasadded to a solution of 7-trifluoromethoxy-1H-indole-2-carboxylic acidethyl ester (1.53 g, 5.6 mmol) and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester (1.53 g, 6.45 mmol) in N,N-dimethylformamide (15 mL) at0° C. The solution was allowed to reach room temperature and stirred 36h. Further amounts of sodium hydride (56 mg) and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester (306 mg) were added to complete the reaction. To thesolution was added 10% aq. citric acid solution and the mixture stirred1 h at room temperature. The organics were extracted with ethyl acetate(2×), the combined organic phases washed with sat. aq. NaHCO₃ solutionand brine, dried (Na₂SO₄), and evaporated. The residue was dissolved indichloromethane (25 mL), cooled to 0° C. and treated withtrifluoroacetic acid (12 mL). After removal of the ice bath, thesolution was stirred for 30 min and evaporated under reduced pressure.The residue was taken up in methanol (20 mL) and K₂CO₃ (2.52 g, 19.5mmol) added, and the mixture stirred 15 h at room temperature. Themixture was filtered, the filtrate diluted with ethyl acetate, washedwith water, dried (Na₂SO₄) and evaporated. The residue was purified bycolumn chromatography on silica gel (hexane/ethyl acetate gradient) toafford the product as a pale yellow foam (89 mg, 64%).

ISP-MS: m/e=285.1 (M⁺+H).

c) 7-Trifluoromethoxy-1H-indole-2-carboxylic acid ethyl ester

The title compound (EI-MS: m/e=273.1 (M-+)) was produced in accordancewith the general method of example 1c to le) from7-trifluoromethoxy-1H-indole. Light brown amorphous solid.

d) 7-Trifluoromethoxy-1H-indole

Potassium hydroxide (17.9 g, 321 mmol) was boiled for 2 h in t-butanol(500 mL). (2-Trifluoromethoxy-6-trimethylsilanylethynyl-phenyl)-carbamicacid ethyl ester (52.8 g, 153 mmol) dissolved in t-butanol (500 mL) wasadded and boiling was continued for 2 h. The solvent was removed invacuo and the residue was partitioned between diethyl ether and water.The organic phases were washed with brine, pooled and dried with MgSO₄.Evaporation of the solvent yielded 31.8 g of a brownish oil, which waspurified by chromatography on silica gel with hexane/ethylacetate (9:1).This yielded the title compound, (30.2 g, 98%) as a yellow oil. (EI-MS:m/e=201.0 (M⁺))

e) (2-Trifluoromethoxy-6-trimethylsilanylethynyl-phenyl)-carbamic acidethyl ester

Bis(triphenylphosphine)palladium(II) dichloride (1.1 g, 1.6 mmol) andcopper(I) iodide (0.3 g, 1.6 mmol) were added to triethylamine (600 mL)and heated with stirring for 20 min. The mixture was cooled to roomtemperature and (2-iodo-6-trifluoromethoxy-phenyl)-carbamic acid ethylester (60.2 g, 160 mmol) was added. After stirring for 30 min at roomtemperature trimethylsilylacetylene (21.1 g, 152 mmol) was added and themixture was stirred for another 2 h at room temperature. Triethylaminewas removed in vacuo and the residue was partitioned between water anddiethyl ether. The organic phases were washed with 1N HCl, brine, pooledand dried with MgSO₄. Evaporation of the solvent yielded 57 g ofbrownish solid, which was purified by chromatography on silica gel withhexane/ethyl acetate (9:1). This yielded the title compound, (52.8 g,95%) as a beige amorphous solid. (EI-MS: m/e=345.0 (M⁺))

f) (2-Iodo-6-trifluoromethoxy-phenyl)-carbamic acid ethyl ester

(2-Trifluoromethoxy-phenyl)-carbamic acid ethyl ester (42.4 g, 0.17 mol)was dissolved in THF (800 mL) and cooled to −70° C. sec-BuLi incyclohexane (280 mL, 1.3 M) was added dropwise at this temperature withstirring. Stirring was continued for 1 h after addition was complete. Asolution of iodine (43.2 g, 0.17 mol) in THF (160 mL) was added dropwiseat −70° C. Stirring was continued for 1 h after addition was completeand the mixture was hydrolysed with saturated ammonium chloridesolution. Water was added and the mixture was extracted with diethylether. The organic phases were washed with 40% sodium bisulfite, water,brine, pooled and dried with MgSO₄. Evaporation of the solvent yieldedthe title compound, (60.2 g, 94%) as a colorless amorphous solid.(EI-MS: m/e=374.9 (M⁺))

g) (2-Trifluoromethoxy-phenyl)-carbamic acid ethyl ester

2-(Trifluoromethoxy)aniline (50 g, 0.282 mol) was dissolved in DME (1000mL) and cooled to −5° C. Sodium hydride (12.3 g, 55%, 0.282 mol) wasadded in portions and the suspension was allowed to warm to roomtemperature. Ethyl chloroformate (23.5 mL, 0.245 mol) was added drop bydrop and the mixture was stirred for 2 h at room temperature and for 1.5h at reflux after addition was complete. Hydrolysis was with water (110mL). The phases were separated and the water phase was extracted withethyl acetate. The organic phases were washed with brine, pooled anddried with MgSO₄. Evaporation of the solvent yielded 70.6 g of a brownoil, which was purified by chromatography on silica gel withhexane/ethyl acetate (6:1). This yielded the title compound, (44.2 g,62%) as a beige yellow oil. (EI-MS: m/e=249.1 (M⁺))

Example 58 and 59(4R,10aR)-6-Fluoro-4,9-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and(4R,10aS)-6-Fluoro-4,9-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) (2-Fluoro-5-methyl-phenyl)-hydrazine

The title compound was prepared in accordance with the general method ofexample 25a) from 2-fluoro-5-methylaniline.

Light yellow solid. EI-MS: m/e=140.2 (M).

b) 2-[(2-Fluoro-5-methyl-phenyl)-hydrazono]-propionic acid ethyl ester

The title compound was prepared in accordance with the general method ofexample 25b) from (2-fluoro-5-methyl-phenyl)-hydrazine and ethylpyruvate.

Light yellow solid. EI-MS: m/e=238.2 (M).

c) 7-Fluoro-4-methyl-1H-indole-2-carboxylic acid ethyl ester

The title compound was prepared in accordance with the general method ofexample 25c) from 2-[(2-fluoro-5-methyl-phenyl)-hydrazono]-propionicacid ethyl ester. Light yellow solid. EI-MS: m/e=221.2 (M).

d)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-7-fluoro-4-methyl-H-indole-2-carboxylicacid ethyl ester

The title compound was prepared in accordance with the general method ofexample 12b) from 7-fluoro-4-methyl-H1-indole-2-carboxylic acid ethylester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester.

Light yellow solid. ISP-MS: m/e=401.4 (M+Na⁺).

e) (R)-6-Fluoro-4,9-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was prepared in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-7-fluoro-4-methyl-1H-indole-2-carboxylicacid ethyl ester.

Light yellow crystals. EI-MS: m/e=232.2 (M).

f)(4R,10aR)-6-Fluoro-4,9-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and

(4R,10aS)-6-Fluoro-4,9-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compounds were prepared in accordance with the general methodof example 25f) from(R)-6-fluoro-4,9-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

(4R,10aR) Isomer: Light yellow crystals. EI-MS: m/e=220.3 (M).

(4R,10aS) Isomer: White crystalline solid. EI-MS: m/e=220.3 (M).

Example 60(4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-6-carbonitrilehydrochloride

The title compound was produced in accordance with the general method ofexample 24a)-c) from(4R,10aR)-6-bromo-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole.

Light yellow crystals. ISP-MS: m/e=214.3 (M+H⁺).

Example 61 and 62(4R,10aR)-6-Chloro-4,8-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and(4R,10aS)-6-Chloro-4,8-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-7-chloro-5-methyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was prepared in accordance with the general method ofexample 12b) from 7-chloro-5-methyl-1H-indole-2-carboxylic acid ethylester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester.

Colorless oil. EI-MS: m/e=394.3 (M).

b) (R)-6-Chloro-4,8-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was prepared in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-7-chloro-5-methyl-1H-indole-2-carboxylicacid ethyl ester.

White crystalline solid. EI-MS: m/e=248.2 (M).

c)(4R,10aR)-6-Chloro-4,8-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride and

(4R,10aS)-6-Chloro-4,8-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compounds were prepared in accordance with the general methodof example 25f) from(R)-6-chloro-4,8-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

(4R,10aR) Isomer: Light yellow crystals. ISP-MS: m/e=237.1 (M+H⁺).

(4R,10aS) Isomer: White crystalline solid. ISP-MS: m/e=237.1 (M+H⁺).

Example 63(4R,10aR)-4,6,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-4,7-dimethyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was prepared in accordance with the general method ofexample 12b) from 4,7-dimethyl-1H-indole-2-carboxylic acid ethyl esterand (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

b) (R)-4,6,9-Trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was prepared in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-4,7-dimethyl-1H-indole-2-carboxylicacid ethyl ester.

c) (R)-4,6,9-Trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound was prepared in accordance with the general method ofexample 12d) from(R)-4,6,9-trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

d)(4R,10aR)-4,6,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=217.3 (M+H⁺) and α_(D)²⁰ = −71.5,was prepared in accordance with the general method of example 12e) from(R)-4,6,9-trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Example 64(4R,10aS)-4,6,7-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (4R,10aS)-4,6,7-Trimethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1 one

The title compound was prepared in accordance with the general method ofexample 14e) from(R)-4,6,7-trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

b)(4R,10aS)-4,6,7-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=217.3 (M+H⁺), α_(D)²⁰ = −5.2,was prepared in accordance with the general method of example 14f)) from(4R,10aS)-4,6,7-trimethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1one.

Example 65(4R,10aS)-4,6,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(4R,10aS)-4,6,9-Trimethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1one

The title compound was prepared in accordance with the general method ofexample 14e) from(R)-4,6,9-trimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

b)(4R,10aS)-4,6,9-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=217.4 (M+H⁺), α_(D)²⁰ = +57.4,was prepared in accordance with the general method of example 14f)) from(4R,10aS)-4,6,9-trimethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1one.

Example 66(4R,10aR)-7-Chloro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (3-Chloro-2-methyl-phenyl)-hydrazine

The title compound was prepared in accordance with the general method ofexample 25a) from 3-chloro-2-methylaniline.

b) 2-[(3-Chloro-2-methyl-phenyl)-hydrazono]-propionic acid ethyl ester

The title compound was prepared in accordance with the general method ofexample 25b) from a) (3-chloro-2-methyl-phenyl)-hydrazine and ethylpyruvate.

c)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-6-chloro-7-methyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was prepared in accordance with the general method ofexample 12b) from 6-chloro-7-methyl-1H-indole-2-carboxylic acid ethylester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester.

d) (R)-7-Chloro-4,6-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was prepared in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6-chloro-7-methyl-1H-indole-2-carboxylicacid ethyl ester.

e) (R)-7-Chloro-4,6-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound was prepared in accordance with the general method ofexample 12d) from(R)-7-chloro-4,6-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

f)(4R,10aR)-7-Chloro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=237.2 (M+H⁺), was prepared in accordancewith the general method of example 12e)(R)-7-chloro-4,6-dimethyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole.

Example 67(4R,10aS)-7-Chloro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(4R,10aS)-7-Chloro-4,6-dimethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was prepared in accordance with the general method ofexample 14e) from(R)-7-chloro-4,6-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

b)(4R,10aS)-7-Chloro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=237.2 (M+H⁺), α_(D)²⁰ = +32.6,was prepared in accordance with the general method of example 14f)(4R,10aS)-7-chloro-4,6-dimethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one.

Example 68 Mixture of (4S,10aS) and(4R,10aR)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (RS)-7-Chloro-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, brownish solid with m.p. 153-155° C., was producedin accordance with the general method of example 14d) from6-chloro-1H-indole-2-carboxylic acid ethyl ester and(RS)-5-ethyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

b) Mixture of (4RS,10aSR) and(4SR,10aRS)-7-chloro-4-ethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was prepared in accordance with the general method ofexample 14e) from a)(RS)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

c) Mixture of (4S,10aS) and(4R,10aR)-7-chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=237.2 (M+H⁺), was prepared in accordancewith the general method of example 14f) from the mixture of (4RS,10aSR)and(4SR,10aRS)-7-chloro-4-ethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-oneand separated from the epimeric mixture by flash chromatography withdichloromethane/methanol (93:7).

Example 69 Mixture of (4S,10aR) and(4R,10aS)-7-chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=237.2 (M+H⁺), was prepared in accordancewith the general method of example 14f) from the mixture of (4RS,10aSR)and(4SR,10aRS)-7-chloro-4-ethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-oneand separated from the epimeric mixture by flash chromatography withdichloromethane/methanol (93:7).

Example 70(4R,10aR)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (R)-7-Chloro-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was isolated from the racemate,(RS)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, bychiral HPLC on a ChiralPak AD column; light brown solid with m.p.162-165° C.

b)(4R,10aR)-7-Chloro-4-ethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-oneand(4R,10aS)-7-chloro-4-ethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one

The title compounds were prepared as a mixture in accordance with thegeneral method of example 14e) from(R)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

c)(4R,10aR)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, EI-MS: m/e=236.1 (M⁺) and α_(D)²⁰ = −29.9,was prepared in accordance with the general method of example 14f) fromthe above mixture and separated from its epimer by flash chromatographywith dichloromethane/methanol (93:7).

Example 71

(4R,10aS)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, EI-MS: m/e=236.1 (M⁺) and α_(D)²⁰ = −80.6,  was prepared in accordance with the general method of example 14f) fromthe mixture obtained in example 70b) and separated from its epimer byflash chromatography with dichloromethane/methanol (93:7).

Example 72(4S,10aS)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (S)-7-Chloro-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was isolated from the racemate,(RS)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, bychiral HPLC on a ChiralPak AD column; yellow solid with m.p. 169-171° C.

b)(4S,10aR)-7-Chloro-4-ethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-oneand(4S,10aS)-7-chloro-4-ethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one

The title compounds were prepared as a mixture in accordance with thegeneral method of example 14e) from(S)-7-chloro-4-ethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

c)(4S,10aS)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=237.2 (M+H⁺) and α_(D)²⁰ = +28.2,was prepared in accordance with the general method of example 14f) fromthe above mixture and separated from its epimer by flash chromatographywith dichloromethane/methanol (93:7).

Example 73(4S,10aR)-7-Chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=37.2 (M+H⁺) and α_(D)²⁰ = −+40.6,was prepared in accordance with the general method of example 14f) fromthe mixture obtained in example 72b) and separated from its epimer byflash chromatography with dichloromethane/methanol (93:7).

Example 74(4R,10aS)-6-Chloro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(4R,10aS)-6-Chloro-4,7-dimethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was prepared in accordance with the general method ofexample 14e) from(R)-6-chloro-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

b)(4R,10aS)-6-Chloro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, EI-MS: m/e=236.1 (M⁺), α_(D)²⁰ = −52.6,was prepared in accordance with the general method of example 14f) from(4R,10aS)-6-chloro-4,7-dimethyl-3,4,10,10a-tetrahydro-2H-pyrazino[1,2-a]indol-1-one.

Example 75(4R,10aR)-6-Chloro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (2-Chloro-3-methyl-phenyl)-hydrazine

The title compound was prepared in accordance with the general method ofexample 25a) from 2-chloro-3-methylaniline.

b) 2-[(2-Chloro-3-methyl-phenyl)-hydrazono]-propionic acid ethyl ester

The title compound was prepared in accordance with the general method ofexample 25b) from (2-Chloro-3-methyl-phenyl)-hydrazine and ethylpyruvate.

c) 7-Chloro-6-methyl-1H-indole-2-carboxylic acid ethyl ester

The title compound was prepared in accordance with the general method ofexample 25c) from 2-[(2-chloro-3-methyl-phenyl)-hydrazono]-propionicacid ethyl ester.

d)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-7-chloro-6-methyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was prepared in accordance with the general method ofexample 12b) from 7-chloro-6-methyl-1H-indole-2-carboxylic acid ethylester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester.

e) (R)-6-Chloro-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was prepared in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-7-chloro-6-methyl-1H-indole-2-carboxylicacid ethyl ester.

f) (R)-6-Chloro-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound was prepared in accordance with the general method ofexample 12d) from(R)-6-chloro-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

g)(4R,10aR)-6-Chloro-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=237.2 (M+H⁺) and α_(D)²⁰ = −111.6,was prepared in accordance with the general method of example 12e) from(R)-6-chloro-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

Example 76(10R,6aS)-10-Methyl-2,3,6,6a,7,8,9,10-octahydro-1H-8,10a-diaza-cyclopenta[c]fluorenehydrochloride

a) 2-[((2,3-Dihydro-1H-inden-4-yl)-hydrazono]-propionic acid ethyl ester

The title compound, ISP-MS: m/e=247.3 (M+H⁺), was prepared in accordancewith the general method of example 25b) from(2,3-hihydro-1H-inden-4-yl)-hydrazine and ethyl pyruvate.

b) 1,6,7,8-Tetrahydro-1-aza-as-indacene-2-carboxylic acid ethyl ester

The title compound, EI-MS: m/e=229.1 (M⁺), was prepared in accordancewith the general method of example 25c) from2-[((2,3-dihydro-1H-inden-4-yl)-hydrazono]-propionic acid ethyl ester.

c)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-1,6,7,8-tetrahydro-1-aza-as-indacene-2-carboxylicacid ethyl ester

The title compound was prepared in accordance with the general method ofexample 12b) from b) 1,6,7,8-tetrahydro-1-aza-as-indacene-2-carboxylicacid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

d)(R)-10-Methyl-2,3,9,10-tetrahydro-1H,8H-8,10a-diaza-cyclopenta[c]fluoren-7-one

The title compound, EI-MS: m/e=240.2 (M⁺), was prepared in accordancewith the general method of example 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-1,6,7,8-tetrahydro-1-aza-as-indacene-2-carboxylicacid ethyl ester.

e)(4R,10aS)-10-Methyl-2,3,6,6a,9,10-hexahydro-1H,8H-8,10a-diaza-cyclopenta[c]fluoren-7-one

The title compound was prepared in accordance with the general method ofexample 14e) from(R)-10-methyl-2,3,9,10-tetrahydro-1H,8H-8,10a-diaza-cyclopenta[c]fluoren-7-one.

f)(4R,10aS)-10-Methyl-2,3,6,6a,7,8,9,10-octahydro-1H-8,10a-diaza-cyclopenta[c]fluorenehydrochloride

The title compound, ISP-MS: m/e=229.2 (M+H⁺), α_(D)²⁰ = −67.8,was prepared in accordance with the general method of example 14f) from(4R,10aS)-10-methyl-2,3,6,6a,9,10-hexahydro-1H,8H-8,10a-diaza-cyclopenta[c]fluoren-7-one.

Example 77(4R,10aR)-N-(4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-7-yl)-acetamide;hydrochloride

a)(4R,10aR)-7-(Benzhydrylidene-amino)-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

A mixture of(4R,10aR)-7-bromo-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (3.0 g, 8 mmol), benzophenone imine (1.52 g, 8mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (85 mg,0.08 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphtalene (153 mg, 0.24mmol) and sodium tert-butylate (1.1 g, 11.4 mmol) in toluene (30 mL) washeated to 80° C. for 3 h. After cooling the mixture was diluted withdiethyl ether (300 mL) and filtered through Celite®. The solvents wereevaporated and the residue was purified by chromatography on silica gelwith ethylacetate/n-hexane (1:4). The title product was isolated asyellowish foam (3.4 g, 89%); ISP-MS: m/e=468.3 (M+H⁺).

b)(4R,10aR)-7-Amino-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

A mixture of(4R,10aR)-7-(benzhydrylidene-amino)-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (3.35 g, 7.2 mmol), ammonium formiate (6.8 g, 107mmol) and palladium on carbon (1.5 g, 5%) in methanol (35 mL) was heatedto 60° C. for 1 h. After cooling the mixture was diluted withdichloromethane (100 mL) and filtered. The filtrate was washed withwater (100 mL), the water phase was extracted with dichloromethane, andorganic phases were pooled and dried with MgSO₄. The solvents wereremoved in vacuo and the residue was purified by chromatography onsilica gel with ethylacetate/n-hexane (1:1). The title product wasisolated as yellow foam (1.15 g, 53%); ISP-MS: m/e=304.4 (M+H⁺).

c)(4R,10aR)-N-(4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-7-yl)-acetamide;hydrochloride

A mixture of(4R,10aR)-7-amino-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (300 mg, 1 mmol), triethylamine (0.3 mL, 2.2 mmol)and acetyl chloride (0.07 mL, 1 mmol) in dichloromethane (6 mL) wasstirred for 30 min. The solvent was removed in vacuo and the residue waspurified by chromatography on silica gel with ethylacetate/n-hexane(1:1) to yield 230 mg of the Boc-protected acetamide. This was thendeprotected by stirring for 1 h in trifluoroacetic acid (2 mL) at roomtemperature. Saturated sodium bicarbonate solution (40 mL) was added andthe mixture was extracted with dichloromethane. Organic phases werepooled, dried with MgSO₄, the solvent was removed in vacuo and theresidue was purified by chromatography on silica gel withdichloromethane/methanol (9:1). The title product was isolated andprecipitated as hydrochloride salt from ethylacetate. Beige solid (97mg, 35%); m.p. >250° C. dec., EI-MS: m/e=245.3 (M⁺).

Example 78(4R,10aR)-(4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-7-yl)-methanol;hydrochloride

a)(4R,10aR)-4-Methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2,7-dicarboxylicacid 2-tert-butyl ester

(4R,10aR)-7-Bromo-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (5.4 g, 15 mmol) was dissolved in tetrahydrofuran(90 mL) and cooled to −78° C. n-Butyllithium (12.8 mL, 1.6 N inn-hexane) was added slowly and the yellow mixture was stirred foranother 30 min at −78° C. after addition was finished. Carbon dioxidegas was bubbled through the mixture for 30 min, cooling was removed andthe mixture was hydrolyzed by adding it to a mixture of ice and water(200 g). 1 N Sodium hydroxide solution (250 mL) was added and themixture washed with diethylether (100 mL). The organic phase wasextracted twice with 1 N sodium hydroxide solution; the water phaseswere pooled and acidified to pH 1.7 with 1 N hydrochloric acid. Thewater phase was extracted with diethylether (3×300 mL), organic phaseswere pooled and dried with MgSO₄. The solvent was evaporated and theresidue was triturated with diethylether/n-hexane (1:3). The titleproduct was isolated as colorless solid (4.1 g, 85%); ISN-MS: m/e=331.3(M⁻); α_(D)²⁰ = −42.8.b)(4R,10aR)-7-Hydroxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

(4R,10aR)-4-Methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2,7-dicarboxylicacid 2-tert-butyl ester (250 mg, 0.75 mmol) was dissolved intetrahydrofuran (5 mL). Lithium aluminium hydride (75 mg, 1.5 mmol) wasadded in portions and the mixture was stirred for 15 min at roomtemperature. Water (0.2 mL), sodium hydroxide solution (0.4 mL, 15%) andwater (0.6 mL) were added sequentially, the mixture was diluted withdiethylether (15 mL) and dried with Na₂SO₄. The solvents were removed invacuo and the residue was purified by chromatography on silica gel withethylacetate/n-hexane (2:1). The title product was isolated as lightyellow oil (163 mg, 68%); ISP-MS: m/e=319.4 (M+H⁺).

c)(4R,10aR)-(4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-7-yl)-methanol;hydrochloride

A mixture of(4R,10aR)-7-hydroxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (160 mg, 0.5 mmol), trifluoroacetic acid (2 mL)and dichloromethane (3 mL) was stirred for 1 h at room temperature.Saturated sodium bicarbonate solution (50 mL) was added and the mixturewas extracted with dichloromethane. Organic phases were pooled, driedwith Na₂SO₄, the solvent was removed in vacuo and the residue wasprecipitated as hydrochloride salt from ethylacetate to yield the titlecompound. Beige solid (84 mg, 65%); m.p. 66° C. dec., ISP-MS: m/e=219.3(M+H⁺).

Example 79(4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-7-carboxylicacid butylamide; hydrochloride

a)(4R,10aR)-7-Butylcarbamoyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

(4R,10aR)-4-Methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2,7-dicarboxylicacid 2-tert-butyl ester (300 mg, 0.9 mmol) was dissolved indichloromethane (5 mL). N-Butylamine (0.45 mL, 4.5 mmol),4-ethylmorpholine (0.57 mL, 4.5 mmol) and BOP (0.42 g, 0.95 mmol) wasadded and the mixture was stirred for 16 h at room temperature. Themixture was added to 1 N hydrochloric acid (20 mL) and extracted withdiethylether (2×50 mL). Organic phases were pooled, washed with water, 2N sodium bicarbonate, water and brine to be finally dried with MgSO₄.The solvents were removed in vacuo to yield the title compound ascolorless foam (346 mg, 98%); ISP-MS: m/e=332.3 (M+H⁺).

b)(4R,10aR)-(4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-7-yl)-methanol;hydrochloride

This compound was prepared in accordance with the general method ofexample 78c) from(4R,10aR)-7-butylcarbamoyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester. White solid. M.p. 125° C. dec.; ISP-MS: m/e=288.3(M+H⁺); α_(D)²⁰ = −43.0.

Example 80(4R,10aR)-4,8-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoletrifluoroacetate

a)(R)-1-(2-tert-Butoxycarbonylamino-1-methyl-ethyl)-5-methyl-1H-indole-2-carboxylicacid ethyl ester

The title compound was prepared in accordance with the general method ofexample 12b) from 5-methyl-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

b) (R)-4,8-Dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound was prepared in accordance with the general method ofexample 12c) from(R)-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-5-methyl-1H-indole-2-carboxylicacid ethyl ester.

c) (R)-4,8-Dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound was prepared in accordance with the general method ofexample 12d) from(R)-4,8-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

d) (4R,10aR)-4,8-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoletrifluoroacetate

The title compound, ISP-MS: m/e=203.2 (M+H⁺) and α_(D)²⁰ = −48.5,was prepared in accordance with the general method of example 12e) from(R)-4,8-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Examples 81 and 82(4R,10aR)-8-Bromo-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoleand(4R,10aS)-8-Bromo-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (4-Bromo-3-methyl-phenyl)-carbamic acid methyl ester

To a solution of 10.00 g 4-bromo-3-methylaniline in 50 mldichloromethane was added 80 ml of a 10% solution of sodium bicarbonatein water. The mixture was cooled to 0° C. and 6.2 ml (7.62 g) methylchloroformate was added during 10 min. with stirring. The reactionmixture was stirred at room temperature for 1 h. The phases wereseparated. The organic phase was washed with a 10% solution of citricacid in water, 10% solution of sodium bicarbonate in water and brine,dried with magnesium sulfate and evaporated to yield 12.94 g of(4-bromo-3-methyl-phenyl)-carbamic acid methyl ester as light brownsolid melting at 71-72° C.

b) (4-Bromo-2-iodo-5-methyl-phenyl)-carbamic acid methyl ester

To a solution of 5.00 g (4-bromo-3-methyl-phenyl)-carbamic acid methylester in 50 ml acetonitrile were added at 0° C. 4.84 g N-iodosuccinimideand 0.18-ml trifluoromethanesulfonic acid. The mixture was stirred 18 hat room temperature. The solid was collected by filtration, washed withcold acetonitrile and dried to constant weight to yield 5.80 g(4-bromo-2-iodo-5-methyl-phenyl)-carbamic acid methyl ester as whitecrystals melting at 140-141° C.

c)(4-Bromo-2-{3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-prop-1-ynyl}-5-methyl-phenyl)-carbamicacid methyl ester

To a solution of 3.70 g (4-bromo-2-iodo-5-methyl-phenyl)-carbamic acidmethyl ester and 0.070 g bis-triphenylphosphine palladium dichloride and0.038 g cuprous iodide in 25 ml triethylamine was added 2.38 g dimethyl(2-propynyloxy)(1,1,2-trimethylpropyl)-silane and the mixture was heated2 h at reflux. The reaction mixture was partitioned between water andethyl acetate. The phases were separated and the organic phase waswashed with 1N hydrochloric acid, sodium bicarbonate and brine, driedwith magnesium sulfate and purified by chromatography on silica gel withhexane:ethyl acetate=4:1 to yield 1.92 g(4-bromo-2-{3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-prop-1-ynyl}-5-methyl-phenyl)-carbamicacid methyl ester as a light brown oil. MS: M+NH₄ ⁺=457.0 M+Na⁺=462.2

d)5-Bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-1H-indole

To a suspension of 0.5144 g lithium hydroxide in 37 ml dimethylsulfoxideand 3.7 ml water was added 1.800 g(4-bromo-2-{3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-prop-1-ynyl}-5-methyl-phenyl)-carbamicacid methyl ester and the mixture was heated 2 h at 80° C. Water andethyl acetate were added. The pH was adjusted to 6.00 by addition ofhydrochloric acid. The phases were separated and the organic phase waswashed with 10% sodium bicarbonate and brine and purified bychromatography on silica gel with hexane:ethyl acetate=9:1 to yield 0.97g5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-1H-indoleas a colorless oil. EI-MS: M=383.1

e)(R)-(2-{5-Bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-indol-1-yl}-propyl)-carbamicacid tert-butyl ester

To a solution of 0.95 g5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-1H-indolein 10 ml N,N-dimethylformamide was added 0.143 g sodium hydride 55-65%in oil and the mixture was stirred 30 min at room temperature. To theresulting mixture was added(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester (0.703 g) and the mixture was stirred 2 h at roomtemperature. The reaction mixture was partitioned between water andethyl acetate. The phases were separated and the organic phase waswashed with 10% citric acid and brine, dried over magnesium sulfate andpurified by chromatography on silica gel with hexane:ethyl acetate=5:1to yield 0.789 g(R)-(2-{5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-indol-1-yl}-propyl)-carbamicacid tert-butyl ester as a slightly yellow oil. ISP-MS: M+H=541.3

f)(R)-8-Bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

A mixture of 0.75 g(R)-(2-{5-bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-methyl-indol-1-yl}-propyl)-carbamicacid tert-butyl ester and 0.52 g ammonium fluoride in 7.5 ml methanolwas stirred 18 h at room temperature. The reaction mixture waspartitioned between water and ethyl acetate. The phases were separatedand the organic phase was washed with 10% citric acid, 10% sodiumbicarbonate and brine, dried over magnesium sulfate and evaporated todryness. The residue was taken up in 6 ml dichloromethane and 0.59 gmanganese dioxide was added. The mixture was stirred 2 h at roomtemperature. The solids were removed by filtration over dicalite and thefiltrate was evaporated to dryness. The residue was taken up in 5 mldichloromethane and 0.072 ml acetic acid and 1.00 g molecular sieve(powder, 4 Å) were added. To the resulting suspension was added 0.536 gtriacetoxyborohydride, and the mixture was stirred 1 h at roomtemperature. Another 0.536 g triacetoxyborohydride was added and themixture was stirred 1 h. The solids were removed by filtration overdicalite and the filtrate was purified by chromatography on silica gelwith hexane:ethyl acetate=2:1 to yield 0.295 g of the title compound asa yellow solid melting at 113-114° C. after crystallisation from hexane.

g) (R)-8-Bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indolehydrochloride

A solution of 0.12 g(R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester in 3 ml of a 2M solution of hydrochloric acid inethyl acetate was stirred at room temperature under argon for 2 h. Theprecipitate was collected by filtration and dried to constant weight toyield the title compound (0.065 g) as off-white crystals. m.p.: 241° C.(dec.); ISP-MS: M+H=279.1; ¹HNMR: (250 MHz, DMSO-d6, δ [ppm]) 1.50 (d,J=6.5 Hz, 3H); 2.45 (s, 3H); 3.48-3.74 (m, 2H); 4.36-4.58 (m, 2H);4.74-4.89 (m, 1H); 6.35 (s, 1H); 7.54 (s, 1H); 7.78(s, 1H)

h)(4R,10aR)-8-Bromo-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoleand(4R,10aS)-8-Bromo-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

In analogy to example 12e) the title compounds were obtained from (R)8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole; byreduction with sodium borohydride in the presence of trifluoroaceticacid. The diastereomeric products were separated by chromatography onsilica gel. The more polar compound was assigned the transconfiguration. The relative stereochemistry was determined on the basisof the proton NMR spectra and the rf. values.

ISP-MS: M+H=281.1 and 283.1

Examples 83 and 84 (4R,10aS)4,7-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole and(4R,10aR) 4,7-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(R)-4,7-Dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

To a solution of 1.52 g(R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester in 15 ml ethanol was added 0.15 g 10% palladium oncharcoal and the mixture was stirred under a hydrogen atmosphere for 6h. A further 0.15 g 10% palladium on charcoal was added and the mixturewas stirred a further 6hunder a hydrogen atmosphere. Again 0.15 g 10%palladium on charcoal was added and the mixture was stirred a further 6h under a hydrogen atmosphere. The catalyst was removed by filtrationover dicalite and the filtrate was evaporated. The residue was purifiedby chromatography on silica gel with hexane:ethyl acetate=4:1 to yield0.59 g(R)-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester as a white foam. MS: (M+H)=301.3.

b) (R)-4,7-Dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indolehydrochloride

The title compound (MS: M+H=201.2; mp.: 245° C. (dec)) was produced inanalogy with method of example 81 from(R)-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester.HNMR: (250 MHz, DMSO-d6, δ [ppm]) 1.51 (d, J=6.5Hz, 3H); 2.43 (s, 3H); 3.50-3.74 (m, 2H); 4.36-4.58 (m, 2H); 4.74-4.89(m, 1H); 6.34 (s, 1H); 6.82 (d, J=7 Hz, 1H); 7.38(s, 1H); 7.41(d, J=7Hz, 1H)

c) (4R,10aS) 4,7-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoleand (4R,10aR)4,7-Dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

In analogy to example 12e the title compounds were obtained from(R)-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester; by reduction with sodium borohydride in thepresence of trifluoroacetic acid. The diastereomeric products wereseparated by chromatography on silica gel. The more polar compound wasassigned the trans configuration. The relative stereochemistry wasdetermined on the basis of the proton NMR spectra and the rf. Values.

MS: M+H=203.2

Examples 85 and 86(4R,10aR)-4,7,8-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indoleand (4R,10aS)4,7,8-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(R)-4,7,8-Trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

To a solution of 1.18 g(R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester in 12 ml dioxane were added 0.36 gtetrakistriphenylphosphinpalladium, 1.29 g potassium carbonate and 0.39trimethylboroxine and the mixture was heated 1 h at reflux. The reactionmixture was partitioned between water and ethyl acetate. The phases wereseparated and the organic phase was washed with 10% sodium bicarbonate,10% citric acid and brine, dried over magnesium sulfate and purified bychromatography on silica gel with hexane:ethyl acetate=3:1 to yield 0.62g(R)-4,7,8-trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester as slightly yellow foam. MS: (M+H)=315.4

b) (R)-4,7,8-Trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound (MS: M+H=215.3) was produced in analogy with themethod of example 81 from(R)-4,7,8-trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester. The material was isolated as the free amine baseby chromatography on silica gel with dichloromethane: methanol:ammonia=9:1:0.1 in the form of a light yellow oil.

HNMR: (250 MHz, CDCl₃, δ [ppm]) 1.47 (d, J=6.5 Hz, 3H); 2.33 (s, 3H);2.38 (s, 3H); 3.07-3.42 (m, 2H); 4.06-4.26 (m, 2H); 4.34-4.42 (m, 1H);6.02 (s, 1H); 7.07 (s, 1H); 7.31(s, 1H)

c) (4R,10aR)4,7,8-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole and(4R,10aS) 4,7,8-Trimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

In analogy to example 12e) the title compounds were obtained from(R)-4,7,8-trimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester; by reduction with sodium borohydride in thepresence of trifluoroacetic acid. The diastereomeric products wereseparated by chromatography on silica gel. The more polar compound wasassigned the trans configuration. The relative stereochemistry wasdetermined on the basis of the proton NMR spectra and the rf. values.

MS: M+H=217.3

Example 87(4R,10aR)-6,7-Dichloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a) (R)-6,7-Dichloro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, m/e=269.2 ([M+H]⁺), was produced in accordance withthe general method of example 14d) from6,7-dichloro-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester. White solid.

b) (R)-6,7-Dichloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, m/e=255.1 ([M-Cl]⁺), was produced in accordance withthe general method of example 12d) from(R)-6,7-dichloro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one andprecipitated as the HCl salt. White solid.

c)(4R,10aR)-6,7-Dichloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=257.0 ([M+H]⁺), was produced inaccordance with the general method of example 12e) from(R)-6,7-dichloro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indolehydrochloride. Light brown oil.

Example 88(4R,10aS)-8-Fluoro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) 7-Bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester

2-Bromo-4-fluoro-phenylhydrazine (20 g, 0.097 mol) was dissolved inethanol and the solution cooled to 0° C. (ice-bath). Ethyl pyruvate(11.3 ml, 0.101 mol) was added dropwise and the solution stirred 15 h atroom temperature. The solvent was evaporated under reduced pressure, andthe residue stirred with hexane. The mixture of hydrazones that formedupon cooling in an ice-bath was filtered and dried under vacuum. Yield24.4 g, 82%. The hydrazone mixture (22 g, 0.073 mol) was dissolved inEaton's reagent (230 ml) and the mixture heated 3 h at 50° C. Themixture was cooled to room temperature, diluted with dichloromethane andadded to saturated aqueous sodium hydrogen carbonate. The phases wereseparated and the aqueous phase extracted twice with dichloromethane.The combined organic phases were washed with water, dried over magnesiumsulfate and evaporated. The residue was taken up in diethyl ether, andhexane added whereupon part of the product precipitated. This wasfiltered and the mother liquor purified by column chromatography onsilica gel (5:1 toluene/hexane eluant) to afford the product as a lightyellow solid (14.1 g, 68%). Mp: 125° C., EI MS: 285.0 (M⁺)

b)(R)-7-Bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-5-fluoro-1H-indole-2-carboxylicacid ethyl ester

The title compound, ISP-MS: m/e=(M+H⁺), was prepared in accordance withthe general method of example 12b) from7-bromo-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (10.0 g, 0.035mol) and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester 10 g, 0.042 mol). The product was isolated as a viscousyellow oil, (10.1 g, 65%); ISP MS: 445.3 (M+H)⁺

c)(R)-6-Bromo-8-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

The title compound was prepared in accordance with the general method ofexample 12c) from(R)-7-Bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-5-fluoro-1H-indole-2-carboxylicacid ethyl ester(8.8 g, 0.0199 mol). Yield: 4.1 g, 70%) White solid, Mp:188° C., ISP-MS: 297.2 (M+H)⁺

d)(R)-8-Fluoro-4,6-dimethyl-1,2,3,4-tetrahydro-2H-pyrazino[1,2-a]indol-1-one

(R)-6-Bromo-8-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one(1.2 g, 4.04 mMol) was dissolved in N,N-dimethylformamide under an argonatmosphere. Tetrakis(triphenylphosphine)palladium (0.45 g, 0.4 mMol) andpotassium carbonate (1.56 g, 12.11 mMol) were added. The mixture wasstirred 5 min at room temperature before the addition oftrimethylboroxine (0.55 ml, 4.04 mMol). The mixture was heated overnightat 110° C., cooled to room temperature and filtered over celite, washingwith tetrahydrofuran. The solvents were evaporated to dryness and theresidue purified by column chromatography on silica gel (1:1 to 3:1ethyl acetate/toluene eluant) to afford the title compound as anoff-white solid, (300 mg, 32%); ISP-MS: 233.1 (M+H⁺)

e)(4R,10aS)-8-Fluoro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound was prepared in accordance with the general method ofexample 25f) from(R)-8-Fluoro-4,6-dimethyl-1,2,3,4-tetrahydro-2H-pyrazino[1,2-a]indol-1-one(106 mg), followed by conversion to the hydrochloride (Ethylacetate/HCl). (Yield: 23 mg, 32%), light brown solid, ISP MS: 221.3(M+H)⁺

Example 89(4R,10aR)-8-Bromo-7-fluoro-4methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(4-Bromo-3-fluoro-phenyl)-carbamic acid methyl ester

The title compound, m.p. 121-122° C., was prepared in accordance withthe general method of example 81a) from 4-bromo-3-fluoroaniline andmethyl chloroformate.

b) (4-Bromo-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester

The title compound, m.p. 101-102° C., was prepared in accordance withthe general method of example 8 lb) from(4-bromo-3-fluoro-phenyl)-carbamic acid methyl ester.

c)5-Bromo-2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-fluoro-1H-indole

The title compound, ISP-MS: m/e=302.0, 300.0 ([M+H]⁺), was prepared inaccordance with the general method of example 81c and d) from(4-bromo-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester.

d)(R)-8-Bromo-7-fluoro-4-methyl-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

The title compound, ISP-MS: m/e=383.2 ([M+H]⁺) and m.p. 116-118° C., wasprepared in accordance with the general method of example 81e and f)from5-bromo-2[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-6-fluoro-1H-indoleand (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

e)(R)-8-Bromo-7-fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, m.p. 232° C., was prepared in accordance with thegeneral method of example 81 g) from(R)-8-bromo-7-fluoro-4-methyl-3,4-dihydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester.

f)(4R,10aR)-8-Bromo-7-fluoro-4methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=287.1, 285.0 ([M+H]⁺), was prepared inaccordance with the general method of example 81h) from(R)-8-bromo-7-fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indoleand separated from its diastereomer by chromatography on silica gel.

Example 90(4R,10aS)-8-Bromo-7-fluoro-4methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=287.1, 285.0 ([M+H]⁺), was prepared inaccordance with the general method of example 81h) from(R)-8-bromo-7-fluoro-4-methyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indoleand separated from its diastereomer by chromatography on silica gel.

Example 91(4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-7-carboxylicacid diethylamide hydrochloride

a)(4R,10aR)-7-Diethylcarbamoyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

The title compound; ISP-MS: m/e=388.3 (M+H⁺), was prepared in accordancewith the general method of example 79a) from(4R,10aR)-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2,7-dicarboxylicacid 2-tert-butyl ester and N,N-diethylamine.

b)(4R,10aR)-4-Methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-7-carboxylicacid diethylamide hydrochloride

The title compound was prepared in accordance with the general method ofexample 78c) from(4R,10aR)-7-diethylcarbamoyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester. Yellowish solid. M.p. 97° C. dec.; ISP-MS:m/e=288.3 (M+H⁺); α_(D)²⁰ = −36.8.

Example 92(4R,10aR)-8-Fluoro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;hydrochloride

a) (R)-8-Fluoro-4,6-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole;hydrochloride

The title compound, ISP-MS: m/e=219.3 ([M-Cl]⁺), was produced inaccordance with the general method of example 12d) from(R)-8-fluoro-4,6-dimethyl-3,4,dihydro-pyrazino[1,2-a]indol-1-one andprecipitated as HCl salt from diethylether solution. Light brown solid.

b)(4R,10aR)-8-Fluoro-4,6-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole;hydrochloride

The title compound, ISP-MS: m/e=221.2 ([M-Cl]⁺) was produced inaccordance with the general method of example 12e) from(R)-8-fluoro-4,6-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole;hydrochloride. Light yellow solid.

Example 93

(4R,10aR)-7-Methoxymethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(4R,10aR)-7-Methoxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

Sodium hydride (55-65% dispersion in mineral oil, 27 mg, 0.67 mmol) wasadded to a solution of(4R,10aR)-7-hydroxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester (200 mg, 0.63 mmol) in N,N-dimethylformamide (5mL) at r.t., then after 1 h iodomethane (89 mg, 0.63 mmol) was added andthe reaction mixture was stirred 2 h at 50° C. After cooling anotherportion of sodium hydride (27 mg, 0.67 mmol) was added, then after theaddition of a second equivalent of iodomethane (89 mg, 0.63 mmol) thereaction mixture was stirred 2 h at 50° C. After cooling the reactionmixture was poured onto ice and extracted with ether (30 mL), theorganic layer was washed with half-saturated brine, dried (MgSO₄), andconcentrated. Chromatography on SiO₂ (Hexane/EtOAc 3:1) yielded thetitle compound (109 mg, 52%). Light yellow oil, ISP-MS: m/e=333.3([M+H]⁺).

b)(4R,10aR)-7-Methoxymethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=233.2 ([M+H]⁺), was produced inaccordance with the general method of example 78c) from(4R,10aR)-7-methoxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester. Light yellow oil.

Example 94(4R,10aR)-7-(2-Methoxy-ethoxymethyl)-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

a)(4R,10aR)-7-(2-Methoxy-ethoxymethyl)-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester

The title compound, ISP-MS: m/e=377.4 ([M+H]⁺), was produced inaccordance with the general method of example 93a) from(4R,10aR)-7-hydroxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester and 2-bromoethyl methyl ether. Light yellow oil.

b)(4R,10aR)-7-(2-Methoxy-ethoxymethyl)-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=277.3 ([M+H]⁺), was produced inaccordance with the general method of example 78c) from(4R,10aR)-7-methoxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylicacid tert-butyl ester. Light yellow oil.

Example 95(4R,10aR)-6-Bromo-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

a) (2-Bromo-3-methyl-phenyl)-hydrazine

The title compound, ISP-MS: m/e=184 and 186.1 (M-NH₃), was prepared inaccordance with the general method of example 25a) from2-bromo-3-methylaniline.

b) 2-[(2-Bromo-3-methyl-phenyl)-hydrazono]-propionic acid ethyl ester

The title compound, ISP-MS: m/e=299.3 and 301.3 (M+H⁺), was prepared inaccordance with the general method of example 25b) from(2-bromo-3-methyl-phenyl)-hydrazine and ethyl pyruvate.

c) 7-Bromo-6-methyl-1H-indole-2-carboxylic acid ethyl ester

The title compound, EI-MS: m/e=281.0 and 283.1 (M), was prepared inaccordance with the general method of example 25c) from2-[(2-bromo-3-methyl-phenyl)-hydrazono]-propionic acid ethyl ester.

d)(R)-7-Bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6-methyl-1H-indole-2-carboxylicacid ethyl ester

The title compound, ISP-MS: m/e=439.1 and 441.3 (M⁺), was prepared inaccordance with the general method of example 12b) from7-bromo-6-methyl-1H-indole-2-carboxylic acid ethyl ester and(S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acidtert-butyl ester.

e) (R)-6-Bromo-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

The title compound, ISP-MS: m/e=291.2 and 293.2 (M⁺), was prepared inaccordance with the general method of example 12c)from(R)-7-bromo-1-(2-tert-butoxycarbonylamino-1-methyl-ethyl)-6-methyl-1H-indole-2-carboxylicacid ethyl ester.

f) (R)-6-Bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole

The title compound, ISP-MS: m/e=277.1 and 279.1 (M+H⁺) was prepared inaccordance with the general method of example 12d) from(R)-6-bromo-4,7-dimethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one.

g)(4R,10aR)-6-Bromo-4,7-dimethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride

The title compound, ISP-MS: m/e=281.2 and 283.2 (M⁺) was prepared inaccordance with the general method of example 12e) from(R)-6-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole.

Examples 96 and 97(4S,10aS)-(7-Trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-4-yl)-methanoland(4S,10aR)-(7-Trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-4-yl)-methanol

a)(R)-5-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester

The title compound was prepared from(R)-{3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-2-hydroxy-propyl}-carbamicacid tert-butyl ester by the general method described in example 12a).It was purified by chromatography on silica gel with hexane ethylacetate mixtures and obtained as viscous colorless oil. MS: m/e=396.1(M⁺). α_(D)²⁰ = +8.26b)(S)-4-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-7-trifluoromethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one

To a solution of 0.700 g ethyl 6-(trifluoromethyl)indole-2-carboxylatein 7 ml DMF was added 0.13 g sodium hydride 55% in oil and the mixturewas stirred at room temperature for 30 min. To the resulting solutionwas added 1.30 g(R)-5-[Dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylicacid tert-butyl ester and the mixture was stirred at room temperaturefor 18 h. The reaction mixture was distributed between 10% citric acidand dichloromethane and the organic phase was purified by chromatographyon silica gel with dichloromethane. The product (1.15 g) was taken up in11 ml TFA was stirred at 0° C. for 45 min. The solvent was evaporatedand the residue was taken up in 10 ml methanol. To the resultingsolution was added 1.00 g potassium carbonate and the mixture wasstirred at room temperature for 3 h. The reaction mixture was purifiedby chromatography on silica gel with ethyl acetate to yield 0.36 g ofthe tiltle compound (m.p.: 143-144° C.) and 0.117 g of its desilylatedanalog (m.p.: 184-185° C.)

c)(S)-(7-Trifluoromethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-4-yl)-methanol

To a solution of 0.240 g(S)-4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-7-trifluoromethyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-onein 3 ml THF was added 1.2 ml of a 1M solution of lithium aluminumhydride in THF. The mixture was heated to reflux for 1 h. The reactionmixture was cooled to room temperature and the 10 ml ethyl acetate and10 ml water was added. The phases were separated and the organic phasewas purified by chromatography on silica gel withdichloromethane:methanol:25% aqueous ammonia=190:10:1 to yield 0.11 g ofthe tile compound as white crystals (m.p.: 126-127).

d)(4S,10aS)-(7-Trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-4-yl)-methanoland(4S,10aR)-(7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-4-yl)-methanol

The title compounds of were obtained from(S)-(7-trifluoromethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-4-yl)-methanolby the general procedure described in example 12e) by reduction withsodium borohydride in trifluoroacetic acid. The diastereomeric productswere separated by chromatography on silica gel withdichloromethane:methanol:25% aqueous ammonia=90:10:1. The more polarcompound was assigned the trans configuration.

(4S,10aR)-Isomer: Light yellow gum. ISP-MS: m/e=273.2 ([M+H]⁺).

(4S,10aR)-Isomer: Light yellow gum. ISP-MS: m/e=273.2 ([M+H]⁺).

Example A

Tablets containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per tablet Compound of formula I 10.0-100.0 mg Lactose 125.0mg Maize starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc  5.0 mg

Example C

Injection solutions can have the following composition:

Compound of formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Water forinjection solutions ad 1.0 ml

1. A compound of formula (I-A):

wherein R¹² and R¹³ are halo, R¹⁴ is hydrogen, R¹⁷ is lower alky andwherein said compound is(4R,10aR)-7-chloro-8-fluoro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indolehydrochloride, or a pharmaceutically acceptable salt, or hydratethereof.
 2. A compound of formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is methyl andwherein said compound is(4R,10aR)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 3. A compoundof formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is methyl andwherein said compound is(4R,10aS)-7-chloro-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 4. A compoundof formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is ethyl andwherein said compound is(4RS,10aRS)-7-bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 5. A compoundof formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is ethyl andwherein said compound is(4RS,10aSR)-7-bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 6. A compoundof formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is ethyl andwherein said compound is(4R,10aR)-7-bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 7. A compoundof formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is ethyl andwherein said compound is(4S,10aS)-7-bromo-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 8. A compoundof formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is ethyl andwherein said compound is7-chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole, or apharmaceutically acceptable salt, or hydrate thereof.
 9. A compound offormula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is ethyl andwherein said compound is(4R,10aR)-7-chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 10. Acompound of formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is ethyl andwherein said compound is(4R,10aS)-7-chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 11. Acompound of formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is ethyl andwherein said compound is(4S,10aS)-7-chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 12. Acompound of formula (I-A):

wherein R¹² is halogen, R¹³ and R¹⁴ are hydrogen, R¹⁷ is ethyl andwherein said compound is(4S,10aR)-7-chloro-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 13. Acompound of formula (I-A):

wherein R¹² is hydrogen, R¹³ and R¹⁴ are independently hydrogen or loweralkyl, R¹⁷ is lower alkyl, and wherein said compound is(4RS,10aSR)-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole, or apharmaceutically acceptable salt, or hydrate thereof.
 14. A compound offormula (I-A):

wherein R¹² is hydrogen, R¹³ and R¹⁴ are independently hydrogen or loweralkyl, R¹⁷ is lower alkyl, and wherein said compound is(4RS,10aRS)-4-ethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole, or apharmaceutically acceptable salt, or hydrate thereof.
 15. A compound offormula (I-A):

wherein R¹² is hydrogen, R¹³ is trifluoromethoxy, R¹⁴ hydrogen, halo orlower alkyl, R¹⁷ is methyl, and wherein said compound is(4R,10aR)-4-methyl-6-trifluoromethoxy-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole,or a pharmaceutically acceptable salt, or hydrate thereof.
 16. Acompound of formula (I-A):

wherein R¹² is hydrogen, R¹³ is trifluoromethyl, R¹⁴ hydrogen, halolower alkyl, R¹⁷ hydroxylower alkyl and wherein said compound is(4S,10aS)-(7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-4-yl)-methanol,or a pharmaceutically acceptable salt, hydrate or ester thereof.
 17. Acompound of formula (I-A):

wherein R¹² is hydrogen, one of R¹³ and R¹⁴ is trifluoromethyl,trifluoromethoxy or cyano and the other is hydrogen, halo or loweralkyl, R¹⁷ is hydroxylower alkyl and wherein said compound is(4S,10aR)-(7-trifluoromethyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indol-4-yl)-methanol,or a pharmaceutically acceptable salt, hydrate or ester thereof.
 18. Thecompound of formula I-B:

wherein one of R²² and R²³ is hydrogen and the other is hydroxy loweralkyl, lower-alkylaminocarbonyl, di-lower alkylaminocarbonyl, alkoxylower alkyl, lower alkylcarbonylamino or lower alkoxy-lower alkoxy loweralkyl; or R²² and R²³ taken together with the carbon atoms to which theyare added to form a 4- to 6-membered saturated carbocyclic ring whichring is unsubstituted or lower alkyl substituted and R²⁷ is lower alkyl;or a pharmaceutically acceptable salt, hydrate or ester thereof.
 19. Thecompound of claim 18 wherein R²² and R²³ form with their attached carbonatoms said carbocyclic ring.
 20. The compound of claim 19 wherein saidcompound is(10R,6aS)-10-methyl-2,3,6,6a,7,8,9,10-octahydro-1H-8,10a-diaza-cyclopenta[c]fluorenehydrochloride.
 21. The compound of claim 18 wherein one of R²² and R²³is hydrogen and the other is hydroxy lower alkyl, loweralkylaminocarbonyl, di-lower alkylaminocarbonyl, lower alkoxy-loweralkyl, lower alkyl carbonylamino or lower alkoxy lower alkoxy loweralkyl.
 22. The compound of claim 21 wherein said compound is(4R,10aR)-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole-7-carboxylicacid diethylamide hydrochloride.
 23. The compound of claim 21 whereinsaid compound is(4R,10aR)-7-methoxymethyl-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole.24. The compound of claim 21 wherein said compound is(4R,10aR)-7-(2-methoxy-ethoxymethyl)-4-methyl-1,2,3,4,10,10a-hexahydro-pyrazino[1,2-a]indole.